WO2010121646A1 - Heterocyclic compounds as mek inhibitors - Google Patents

Heterocyclic compounds as mek inhibitors Download PDF

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Publication number
WO2010121646A1
WO2010121646A1 PCT/EP2009/054717 EP2009054717W WO2010121646A1 WO 2010121646 A1 WO2010121646 A1 WO 2010121646A1 EP 2009054717 W EP2009054717 W EP 2009054717W WO 2010121646 A1 WO2010121646 A1 WO 2010121646A1
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Prior art keywords
fluoro
phenylamino
tetrahydro
oxo
carboxylic acid
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PCT/EP2009/054717
Other languages
French (fr)
Inventor
Dinesh Chikkanna
Clive Mccarthy
Henrik Moebitz
Chetan Pandit
Ramesh Sistla
Hosahalli Subramanya
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Novartis Ag
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Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to CA2761108A priority Critical patent/CA2761108A1/en
Priority to JP2012506346A priority patent/JP2012524114A/en
Priority to BRPI0925050-6A priority patent/BRPI0925050A2/en
Priority to KR1020117027486A priority patent/KR20120028882A/en
Priority to EA201101533A priority patent/EA201101533A1/en
Priority to PCT/EP2009/054717 priority patent/WO2010121646A1/en
Priority to AU2009344690A priority patent/AU2009344690A1/en
Priority to MX2011011083A priority patent/MX2011011083A/en
Priority to EP09779322A priority patent/EP2421612A1/en
Priority to CN2009801598607A priority patent/CN102458580A/en
Publication of WO2010121646A1 publication Critical patent/WO2010121646A1/en

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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems

Definitions

  • the invention relates to compounds which are specific inhibitors of kinase activity of MEK.
  • the invention also relates to the use of the compounds, their pro-drugs or pharmaceutically acceptable composition comprising the compound or their prodrug in the management of hyperproliferative diseases like cancer and inflammation.
  • Hyperproliferative diseases like cancer and inflammation are attracting the scientific community to provide therapeutic benefits. In this regard efforts have been made to identify and target specific mechanisms which play a role in proliferating the diseases.
  • MAP kinase cascade Over-activation of mitogen-activated protein (MAP) kinase cascade is known to play an important role in cell proliferation and differentiation. This pathway can be activated when a growth factor binds to its receptor tyrosine kinase. This interaction promotes RAS association with RAF and initiates a phosphorylation cascade through MEK (MAP kinase kinase) to ERK. Inhibition of this pathway is known to be beneficial in hyperproliferative diseases. MEK is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERKl and ERK2. Constitutive activation of MEK/ERK was been found in pancreatic, colon, lung, kidney and ovarian primary tumor samples.
  • Phosphorylation of MEK appears to increase its affinity and its catalytic activity toward ERK as well as is affinity for ATP.
  • This invention describes compounds that inhibit MEK activity by modulation of ATP binding, association of MEK with ERK by mechanisms that are competitive, and/or allosteric and/or uncompetitive.
  • the invention provides a compound of formula I
  • X represents Ci-3-alkylene, -N(R 6 )-, -O-, or -S(O) P -;
  • R 1 represents aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said rings are optionally substituted by one or more groups independently selected from List 1;
  • R 2 represents H, cyano, or the group -Y-R 7 ;
  • R 3 and R 4 independently represent H, Ci_ 6 -alkyl, Ci_ 6 -haloalkyl, Ci_ 6 -hydroxyalkyl, hydroxyl, Ci_6.alkoxy, amino, Ci_6-alkylamino, diCi_6-alkylamino, or R 3 additionally represents monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings are optionally substituted by one or more groups independently selected from List 1;
  • R 5 represents H, halogen, Ci_ 3 -alkyl, Ci_ 3 alkoxy, -SCi_ 3 alkyl, or Ci_ 3 -haloalkyl;
  • Y represents a group selected from -D-, -E-, -D-E-, or -E-D-;
  • E represents a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said rings are optionally substituted by one or more groups independently selected from List 1;
  • R 7 represents H, Ci- 6 -alkyl, C 2 - 6 _alkenyl C 2 - 6 _alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein R 7 when not H is optionally substituted by one to three groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy, C 2 - C 6 -alkenyloxy, C 2 -C 6 -alkynyloxy, Ci_6-thioalkyl, Ci- ⁇ haloalkyl, amino, Ci_6alkylamino, di- Ci_6alkylamino, Ci_6acylamino, Ci_6acylCi_6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings may be optionally substituted by one or two groups independently selected from halogen, cyano, hydroxyl, Ci_6.alkoxy, C 2
  • Z is O or N(R 18 );
  • List 1 is selected from hydroxyl, cyano, nitro, Ci- 6 -alkyl, C 2 - 6 .alkenyl, C 2 - 6 .alkynyl, Cp 6 - alkoxy, C 2 - 6 _alkenyloxy, C 2 - 6 _alkynyloxy, halogen, Cp 6 _alkylcarbonyl, carboxy, Cp 6 . alkoxycarbonyl, amino, Ci-6.alkylamino, di-Ci-6.alkylamino, Ci-6-alkylaminocarbonyl, di-Cp 6 .
  • alkylaminocarbonyl Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6.alkyl)amino, Cp 6 .
  • alkylsulfonylamino Ci-6-alkylsulfonyl(Ci- 6 -alkyl)amino
  • Ci- 6 -thioalkyl Ci- 6 -alkylsulfinyl, Cp 6 .
  • alkylsulfanyl Ci- 6 .alkylsulfonyl, aminosulfonyl, Ci- 6 .alkylaminosulfonyl and di-Ci- 6 - alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci-6_alkoxy, amino, Ci-6.alkylamino, di-Cr ⁇ - alkylamino or cyano;
  • R 26 represents H, Ci_ 6 -alkyl, Ci_ 6 -haloalkyl, Ci_ 6 -hydroxyalkyl, hydroxyl, Ci_ 6 .alkoxy, amino, Ci_6-alkylamino, or diCi_6-alkylamino;
  • R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 R 18 , R 24 , and R 25 are independently H or Cj-e-alkyl;
  • p 0, 1, or 2;
  • Alkyl or alkylene means a straight chain, branched and/or cyclic hydrocarbon from 1 to 20 carbon atoms. Alkyl moieties having from 1 to 5 carbons are referred to as "lower alkyl" and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, and isobutyl.
  • Aryl or arylene represents a 6-14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic or one of the bicyclic rings is aromatic and the other ring may be aromatic, saturated or partially unsaturated and may include one to three ring members selected from -C(O), -N(R 19 )q-, -O- and S(O)r where R 19 is H or Ci_ 6 -alkyl, q is 0-1 and r is 0-2;
  • Heteroaryl or heteroarylene represents a 5-14 membered monocyclic or bicyclic ring, wherein the monocyclic or one of the bicyclic rings is an aromatic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, and the other ring may be aromatic, saturated or partially unsaturated, and may include one to three ring members selected from -
  • X represents -N(H)-.
  • R 1 represents optionally substituted phenyl.
  • optional substitution on R 1 is represented by one to three groups independently selected from halogen, e.g. fluoro, bromo or iodo, Ci_6-alkyl, e.g. ethyl, C 2 - 6 -alkynyl, e.g. ethynyl, Ci_ 6 -haloalkyl, e. g trifluoromethyl and Ci_ 6 -thioalkyl, e.g. thiomethyl.
  • halogen e.g. fluoro, bromo or iodo
  • Ci_6-alkyl e.g. ethyl
  • C 2 - 6 -alkynyl e.g. ethynyl
  • Ci_ 6 -haloalkyl e.g trifluoromethyl
  • Ci_ 6 -thioalkyl e.g. thiomethyl.
  • R 1 is represented by phenyl substituted in the 2-, 4- and optionally 6- positions, suitably the 2- and 4- positions.
  • R 1 is represented by phenyl substituted by 2-fluoro and 4-bromo, or, 4-iodo-2-fluorophenyl, or any combination of 2- and 4- substititutuions of iodo, trifluoromethyl, thiomethyl, ethynyl or ethyl.
  • -D- represents a group selected from -C(O)-,-CO 2 -, C(O)N(H)O-, -C(0)N(Ci_6-alkyl)0-, -C(O)N(H)- and -C(O)N(C i-e-alkyl)-.
  • -E- represents a 5-membered heteroarylene or 5-membered heterocycloalkylene.
  • E represents a ring selected from;
  • Y represents -D-E-
  • -D- may represent -C (O) N (H)-
  • -E- may represent optionally substituted cycloalkyl, e.g. cyclopentyl or optionally substituted heteroaryl, e.g. thiazole.
  • Y represents -E-D-
  • -E- may represent optionally substituted heteroaryl, e.g. oxadiazole and -D- may represent -C(O)N(H)-
  • Y represents the groups -D- or -E-.
  • R 7 represents H, d- ⁇ -alkyl, e.g. methyl or ethyl, substituted Ci- 6-alkyl, e.g. by one to three, in another embodiment one to two, groups selected from hydroxyl, including di-hydroxyl, Ci_6-alkoxy, e.g. methoxy, C 2 -C 6 -alkenyloxy, e.g. ethenyloxy, di-Ci_6-alkylamino, e.g. dimethylamino, Ci_6-acylamino, e.g. acetylamino, and optionally substituted monocyclic cycloalkyl, e.g. cyclopropyl.
  • Ci_6-alkoxy e.g. methoxy
  • C 2 -C 6 -alkenyloxy e.g. ethenyloxy
  • di-Ci_6-alkylamino e.g. dimethylamino
  • R 7 represents H, methyl, ethyl, cyclopropylmethyl, 2- hydroxy ethyl, 2-ethenyloxy ethyl, 3-hydroxypropyl, 2-methoxy ethyl, acetylaminomethyl, 2-dimethylamino ethyl or 2,3-dihydroxypropyl.
  • R 2 represents -CO 2 H, COH, -CO 2 Et, C(O)N(H or CH 3 )OR 7a , where R 7a represents methyl, ethyl, cyclopropylmethyl, 2-ethenyloxyethyl, 2- hydroxyethyl and 2,3-dihydroxypropyl, -C(O)N(H or CH 3 )R 711 , where R 7b represents H, methyl, ethyl, cyclopropylmethyl, 2-methoxy ethyl, 2-hydroxy ethyl, 3- hydroxypropyl, acetylamino methyl, 2-dimethylaminoethyl, cyclopentyl or 2-thiazolyl, or R 2 represents oxadiazolylamino.
  • the present invention includes compounds of formula I where R 2 represents CONHOR 7a where R 7a represents cyclopropylmethyl, or 2-hydroxyethyl.
  • n and n are both 1 or one of m and n is 1 and the other is 2.
  • R 3 and R 4 represent H.
  • R 5 represents H, halogen, e.g. fluoro or chloro, Ci_3alkoxy, e.g., methoxy, or ethoxy, -SCi_ 3 alkyl, e.g., SCH 3 , or Ci_ 3 alkyl, e.g. methyl or ethyl.
  • R 5 is fluoro.
  • R 5 is methyl.
  • Z represents O
  • aryl or arylene represent an optionally substituted phenyl or phenylene, respectively.
  • cycloalkyl or cycloalkylene represent an optionally substituted 3-7 membered saturated monocyclic carbocyclic ring, e.g. cyclopropyl or cyclopentyl.
  • heteroaryl or heteroarylene represent an optionally substituted 5-6 membered monocyclic aromatic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, e.g. tetrazolyl, thiazolyl or oxadiazolyl.
  • heterocycloalkyl or heterocycloalkylene represent an optionally substituted 5-6 membered saturated monocyclic ring comprising one or two ring members selected from -N(R 22 )-, -O- and -S(O) 1 -.
  • the compound forms a pharmaceutically acceptable salt, selected from a group comprising acid addition salts and base addition salts.
  • the present invention includes a pharmaceutical composition comprising a compound of formula I or Id and a pharmaceutically acceptable carrier or excipient.
  • the present invention includes a pharmaceutical composition comprising a compound of formula I or Id in combination with a second active agent, and a pharmaceutically acceptable carrier or excipient.
  • the present invention includes compounds of formula Id:
  • Rd 1 represents H, halogen, Ci_ 3 _alkyl, or Ci_ 3 _haloalkyl
  • Rd 2 represents H, cyano, or the group -Y-Rd 5 ;
  • Rd 3 and Rd 4 independently represent hydroxyl, cyano, nitro, Ci- 6 .alkyl, C 2 -6-alkenyl, C 2 -e- alkynyl, d-6-alkoxy, C 2 -6.alkenyloxy, C 2 -6.alkynyloxy, halogen, d-6-alkylcarbonyl, carboxy, Ci-6_alkoxycarbonyl, amino, Ci-6-alkylamino, di-Ci-6-alkylamino, Ci-6-alkylaminocarbonyl, di- Ci-6-alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci- 6 -alkyl)amino, Cp 6 .
  • alkylsulfonylamino Ci-6-alkylsulfonyl(Ci-6.alkyl)amino, Ci-6-thioalkyl, Ci-6-alkylsulfmyl, Ci-&. alkylsulfanyl, Ci- 6 .alkylsulfonyl, aminosulfonyl, Ci- 6 .alkylaminosulfonyl and di-Cr ⁇ - alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci- 6 .alkoxy, amino, Ci- 6 -alkylamino, di-Ci- 6 . alkylamino or cyano;
  • Y represents a group selected from -D-, -E-, -D-E-, or -E-D-;
  • E represents a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said rings are optionally substituted by one or more groups independently selected from List 1 as defined herein;
  • Rd 5 represents H, Ci- 6 -alkyl, C 2 - 6 _alkenyl C 2 - 6 -alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein Rd 5 when not H is optionally substituted by one to three groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy, C 2 -C 6 -alkenyloxy, C 2 -C 6 -alkynyloxy, Ci_6-thioalkyl, Ci- ⁇ haloalkyl, amino, Ci_6alkylamino, di-Ci_6alkylamino, Ci_6acylamino, Ci_6acylCi_6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings may be optionally substituted by one or two groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy,
  • Rd 6 and Rd 7 independently represent hydroxyl, cyano, nitro, Ci- 6 -alkyl, C 2 - 6 .alkenyl, C 2 - 6 . alkynyl, d-6-alkoxy, C 2 -6_alkenyloxy, C 2 -6_alkynyloxy, halogen, Ci-6.alkylcarbonyl, carboxy, Ci-6_alkoxycarbonyl, amino, Ci-6.alkylamino, di-Ci-6.alkylamino, Ci-6-alkylaminocarbonyl, di- Ci-6-alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6.alkyl)amino, Cp 6 .
  • alkylsulfonylamino Ci-6-alkylsulfonyl(Ci- 6 -alkyl)amino, Ci- 6 -thioalkyl, Ci- 6 -alkylsulfinyl, Cp 6 .
  • alkylsulfanyl Ci- 6 .alkylsulfonyl, aminosulfonyl, Ci- 6 .alkylaminosulfonyl and di-Cr ⁇ - alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci-6_alkoxy, amino, Ci-6.alkylamino, di-Cr ⁇ - alkylamino or cyano;
  • j and g independently represent O, 1, 2, or 3;
  • Rd 8 , Rd 9 , Rd 10 , Rd 11 , Rd 12 , Rd 13 , Rd 14 , Rd 15 , Rd 16 , Rd 17 , Rd 18 , and Rd 19 are independently H or Ci_ 6 -alkyl.
  • j is 0, 1, or 2
  • g is 1, 2, or 3.
  • j is 0, and g is 0, 1, or 2.
  • alkyl, alkenyl, alkynyl, and alkoxy groups containing the requisite number of carbon atoms, can be unbranched or branched.
  • alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, i-butoxy, sec-butoxy and t-butoxy.
  • Halogen or "halo” may be fluorine, chlorine, bromine or iodine.
  • Ci-6-haloalkyl refers to an alkyl group substituted by up to seven halogen groups, e.g. fluoro groups.
  • halogen groups e.g. fluoro groups
  • common haloalkyl groups are trifluoroalkyl, 2, 2, 2-trifluoroethyl or 2, 2, 2, 1, 1-pentafluoroethyl groups.
  • alkenyl refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon double bond.
  • C 2 -C 6 -alkenyl refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon double bond.
  • alkynyl refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond.
  • C 2 -C 6 -alkynyl refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon triple bond.
  • alkoxy refers to a group in which an alkyl group is attached to oxygen, wherein alkyl is as previously defined.
  • cycloalkyl groups as defined in formula (I) include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • aryl groups as defined in formula (I) include phenyl, naphthyl, anthracyl and phenanthryl.
  • heterocycloalkyl groups as defined in formula I include [1, 3] dioxolane, [1, 4] dioxane, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, thiomorpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.
  • Examples of monocyclic heteroaryl groups as defined in formula (I) groups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.
  • Examples of bicyclic heteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl, isoindolyl, indolizinyl, benzamidazolyl, and quinolinyl.
  • the compound is a stereoisomer or a tautomer.
  • a suitable individual compound of the invention is selected from: 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l, 2, 3, S-tetrahydro-indolizine-S-carboxylic acid ethyl ester;
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, , propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p- hydroxybenzoic acid, l-hydroxynaphthalene-2-carboxylic acid or 3- hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulf
  • Compounds of formula I and Id which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula I and Id by known salt-forming procedures.
  • the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
  • the present invention embraces both individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof.
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) and (Id) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (I) and (Id) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations Sections using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the invention provides, in another aspect, a process for preparing a compound of formula (I) and (Id).
  • the schemes detailed below show general schemes for synthesizing compounds of formula (I) and (Id). It is recognized that the compounds corresponding to the Roman numerals in the schemes do not correspond to the Roman numerals of claimed compounds.
  • Compounds of formula II may be converted into compounds of formula III by reaction with a halogenating agent such as phosphorus oxybromide, neat or in a suitable solvent such as toluene, at temperatures ranging from room temperature to 14O 0 C.
  • a halogenating agent such as phosphorus oxybromide
  • a suitable solvent such as toluene
  • compounds of formula II may be reacted with nonafluorobutane sulphonyl fluoride in the presence of a base such as diisopropyl ethylamine and a catalyst, such as N,N-dimethyl-4-aminopyridine, in a solvent such as dichloro methane, at room temperature, or with N-phenyltrifluoromethanesulfonimide in the presence of a base, such as diisopropylethyl amine, in a suitable solvent, such as 1,2- dimethoxy ethane, at temperatures ranging from room temperature to the refluxing temperature of the solvent.
  • compounds of formula II may be treated with trifluromethanesulphonic acid anhydride in the presence of base, such as pyridine, in a solvent, such as dichloromethane, at temperatures ranging from -2O 0 C to ambient temperature.
  • Compounds of formula IV may be obtained from compounds of formula III by reaction with appropriate anilines or phenols or thiophenols, using Buchwald-Hartwig C-N/S/O coupling conditions.
  • the Buchwald-Hartwig reactions may be performed in presence of a catalyst such as tris(dibenzylidineacetone)dipalladium (0) or palladium acetate, a base such as potassium phosphate, sodium tert-butoxide, 1.8-diazobicyclo[5.4.1]undec- 7-ene or cesium carbonate, a ligand such as 9,9'-dimethyl-4,5-bis(diphenylphosphino)- xanthene, 2,2'-bis(diphenylphosphino)-l-l '-binaphthyl, 2-dicyclohexylphosphino-2'- (N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2
  • Compounds of formula V can be obtained from compounds of formula IV by reaction with a base such as sodium hydroxide in a protic solvent such as ethanol or methanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent.
  • a base such as sodium hydroxide
  • a protic solvent such as ethanol or methanol
  • Compounds of formula V can be treated with a functionalized hydroxylamine or an amine and a suitable coupling agent, such as O-(7-azabenzo-triazol-l-yl)-N,N,N',N'- tetra-methyluronium hexafluorophosphate, N-(3 -dimethylaminopropyl)-N ' - ethylcarbodimidime hydrochloride or N,N-dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole, with a suitable base such as diisopropylethylamine or triethylamine, in an aprotic solvent such as tetrahydrofuran, N,N-dimethylformamide, or dichloromethane, at temperatures ranging from O 0 C to room temperature, to obtain the compounds of formula VI.
  • a suitable coupling agent such as O-(7-azabenzo-triazol-l-yl
  • compounds of formula VI can be obtained directly from compounds of formula IV by reaction with an amine or hydroxylamine in the presence of a Lewis acid such as trimethyl aluminum, in a solvent such as dichloromethane, at temperatures ranging from room temperature to the refluxing temperature of the solvent.
  • a Lewis acid such as trimethyl aluminum
  • Compounds of formula III can be converted to compounds of formula VII by electrophilic halogenation using reagents such as [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)] in a suitable solvent, such as acetonitrile, at temperatures ranging from room temperature to 7O 0 C.
  • reagents such as [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)] in a suitable solvent, such as acetonitrile, at temperatures ranging from room temperature to 7O 0 C.
  • Compounds of formula VII can be converted into compounds of formula VIII using the conditions as described for the preparation of compounds of formula IV (scheme 1).
  • Compounds of formula VIII can be converted into compounds of formula IX using the conditions as described for the preparation of compounds of formula V (scheme 1).
  • Compounds of formula IX can be converted into compounds of formula X using the conditions as described for the preparation of compounds of formula VI (scheme 1).
  • compounds of formula X can be obtained directly from compounds of formula VIII by reaction with an amine or a hydroxylamine using the conditions as described for the preparation of compounds of formula VI (scheme 1)
  • Compounds of formula XI may be prepared from compounds of formula II by reacting the latter with a base such as NaH and an alkylating agent such as methyl iodide or a halogenating agents such as deoxyfluor, NCS, NBS, NIS, in a suitable solvent such as THF or DMF, at temperatures ranging from room temperature to 10O 0 C.
  • a base such as NaH
  • an alkylating agent such as methyl iodide or a halogenating agents such as deoxyfluor, NCS, NBS, NIS
  • a suitable solvent such as THF or DMF
  • Compounds of formula XII can be obtained from compounds of formula VII by reaction with a base such as sodium or lithium hydroxide in a protic solvent such as ethanol or methanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent.
  • a base such as sodium or lithium hydroxide
  • a protic solvent such as ethanol or methanol
  • Compounds of formula XII can then be converted into compounds of formula IX using an S N AR reaction.
  • the latter is carried out in a suitable solvent such as THF, using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures, typically ranging from -78 0 C to room temperature.
  • Aldehydes and ketones of formula XVI can be prepared from acids of formula IX using the standard methods, such as converting the acids into corresponding Weinreb amide, followed by treatment with appropriate organo -metallic reagents.
  • Oxadiazoles of formula XVII can be prepared by acylating the respective amidoxime, followed by dehydrative cyclization.
  • Acyl azides of formula XVIII can be prepared from compounds of the general formula IX via the acid halide, for example the acid chloride using standard conditions.
  • the formula XVIII compounds can then be transformed via the Curtius rearrangement to give compounds of the general formula XIX.
  • Formula XX compounds can be treated with trimethylsilyl azide or NaN 3 in a suitable aprotic solvent such as N, N-dimethylformamide, at temperatures ranging from room temperature to 100 0 C to yield compounds of formula XXI.
  • a BRAF-MEK-ERK cascade assay is used to evaluate the effects of these compounds as inhibitors of the MAP kinase pathway.
  • An enzymatic cascade assay is set up using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557), human full length unactive MEKl kinase (Cat No. 14-706) and human full length unactive MAP Kinase 2/ERK2 (Cat No. 14-536) enzymes procured from Upstate.
  • TR-FRET Time resolved fluorescence resonance energy transfer
  • the assay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgC12 , 1 mM DTT, 0.01 % Tween 20, 0.1 nM activated BRAF, 2 nM unactive MEKl,10 nM unactive ERK2, 100 ⁇ M ATP and 500 nM long chain biotin-peptide substrate (LCB- FFKNIVTPRTPPP) in a 384 well format.
  • the kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu- labeled phospho- serine/threonine antibody (Cat. No.AD0176-Perkin Elmer), 20 nM SA-APC (Cat No.
  • the TR-FRET signal (Excitation at 340 nm, Emission at 615 nm and 665 nm) is read with 50 ⁇ s delay time on a Victor3 V fluorimeter. The data is calculated using the ratio of readings at 665nm to 615 nm.
  • the final concentration of DMSO is 2.5 % in the assay.
  • Compounds are screened at 10 ⁇ M concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
  • Each individual IC50 is determined using a 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response (variable slope).
  • An in-vitro MAP kinase assay is set up using activated MAP kinase 2/ERK2 (Cat. No.14-550) obtained from Upstate. TR-FRET detection technology is used for the read out.
  • the assay buffer solution contains 50 rnM Tris pH 7.5, 10 rnM MgC12 , 1 rnM DTT, 0.01 % Tween 20, 1 nM activated ERK2, 100 ⁇ M ATP and 500 nM long chain biotin- peptide substrate (LCB- FFKNI VTPRTPPP) in a 384 well format.
  • the kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu- labeled phospho-serine/threonine antibody (Cat.No. AD0176-Perkin Elmer), 20 nM SA-APC (Cat. No. CR130-100-Perkin Elmer) is added.
  • the TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read with 50 ⁇ s delay time on Victor3 V fluorimeter. The data is calculated using the ratio of readings at 665nm to 615 nm.
  • the final concentration of DMSO is 2.5 % in the assay. Compounds are screened at 10 ⁇ M concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
  • the radioactive filter binding assay is standardized using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557) and kinase dead MEKl (K97R) ( Cat No. 14- 737) procured from Upstate.
  • the incorporation of 32P into MEKl (K97R) by BRAF (V599E) is measured with final assay buffer conditions of 50 mM Tris pH 7.5, 10 mM MgC12 , 1 mM DTT, 100 mM sucrose, 100 ⁇ M sodium orthovanadate,5 ⁇ M ATP and 2 ⁇ Ci [ ⁇ 32P] ATP and 500 mg MEKl Kinase dead substrate.
  • the enzymatic reaction is stopped after 120 minutes with 8N HCl (hydrochloric acid) and 1 mM ATP.
  • the solution is spotted on P81 filter paper and washed 4 times with 0.75 % orthophosphoric acid and lastly with acetone.
  • the dried P81 filter papers are read in a Micro-beta Trilux scintillation counter.
  • the final concentration of DMSO is 1 % in the assay.
  • Compounds are screened at 10 ⁇ M concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
  • the cell viability assay in A375 cells is set up in a 96-well plate format using XTT.
  • XTT is a yellow tetrazolium salt that is cleaved to an orange formazan dye by the mitochondria of metabolically active cells. The procedure allows for rapid determination in a microtitre plate, to give reproducible and sensitive results.
  • A375 cells are grown in DMEM media containing 10% FBS and ImM sodium pyruvate. Cells are trypsinized and seeded at 1000 cells/well. After allowing the cells to adhere overnight, compound is added to the wells at the following final concentrations: 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001, and 0.0001 ⁇ M. The assay is set up in triplicates for each concentration. DMSO concentrations are kept at 0.5% /well. Three days after compound addition, the XTT assay is performed. Wells are washed once with PBS. 100 ⁇ L of DMEM media without phenol red or FBS is added to each well.
  • a working solution of XTT containing lmg/ml XTT and 100 ⁇ L of PMS (stock concentration 0.383 mg/ml) per 5ml is prepared. 50 ⁇ L of the working solution of XTT is added to each well. Absorbance of the plate is read at 465nm using a Spectramax 190 (Molecular Devices). The absorbance from wells with media and XTT alone, but without cells is considered the blank and subtracted from readings from all wells.
  • Percentage viability is calculated considering the blank subtracted value from wells treated with DMSO alone as 100% viable.
  • GI50 values are calculated using Graphpad Prism, using non-linear regression curve fit for sigmoidal dose response (variable slope).
  • the cell viability assay is further described in Scudiero, et. al., Cancer Research (1988) 48, 4827-4833; Weislow, et. al., J. Natl. Cancer Institute, (1989) 81, 577-586; and Roehm, et. al., J. Immunol.Methods [1991]142:257-265.
  • the compounds of the present invention are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the Raf/Ras/Mek pathway.
  • the invention relates to a method for treating a disease or condition related to the hyperactivity of MEK, or a disease or condition modulated by the MEK cascade, comprising administration of an effective therapeutic amount of a compound of formula (I) or (Id) or a pharmaceutically acceptable salt thereof.
  • the invention relates to a method for treating proliferative diseases, such as cancer, comprising administration of an effective amount of a compound of formula (I) or (Id) or a pharmaceutically acceptable salt thereof.
  • cancers include but are not limited to: angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma; bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, lymphoma, chondromatous hanlartoma, mesothelioma, esophageal squamous cell carcinoma, leiomyosarcoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, vipoma, stomach and small bowel carcinoid tumors, adenocarcinoma, Karposi's sarcoma, leiomyoma, heman
  • the invention may also be useful in the treatment of other diseases or conditions related to the hyperactivity of MEK.
  • the invention relates to a method of treatment of a disorder selected from: xenograft (cellos), skin, limb, organ or bone marrow transplant) rejection; osteoarthritis; rheumatoid arthritis; cystic fibrosis; complications of diabetes (including diabetic retinopathy and diabetic nephropathy); hepatomegaly; cardiomegaly; stroke (such as acute focal ischemic stroke and global cerebral ischemia); heart failure; septic shock; asthma; chronic obstructive pulmonary disorder; Alzheimer's disease; and chronic or neuropathic pain.
  • a disorder selected from: xenograft (cellos), skin, limb, organ or bone marrow transplant) rejection; osteoarthritis; rheumatoid arthritis; cystic fibrosis; complications of diabetes (including diabetic retinopathy and diabetic nephropathy); hepatomega
  • chronic pain for purposes of the present invention includes, but is not limited to, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic pain is associated with numerous conditions including, but not limited to, inflammation, and post-operative pain.
  • neurodegeneration pain is associated with numerous conditions which include, but are not limited to, inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, and nerve injury between the peripheral nervous system and the central nervous system.
  • Compounds of the invention may also be useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV) human papilloma virus (HPV), cytomegalovirus (CMV], and Epstein-Barr virus (EBV).
  • Compounds of the invention may also be useful in the treatment of restenosis, psoriasis, allergic contact dermatitis, autoimmune disease, atherosclerosis and inflammatory bowel diseases, e.g. Crohn's disease and ulcerative colitis.
  • An MEK inhibitor of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined above may be administered simultaneously, sequentially or separately in combination with one or more agents selected from chemotherapy agents, e.g. mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents, e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(l H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.
  • chemotherapy agents e.g. mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine
  • Such combinations may offer significant advantages, including synergistic activity, in therapy.
  • a compound of the formula (I) or (Id) may also be used to advantage in combination with other antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors, such as LBH589; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors, such as RADOOl; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti- angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; he
  • tumor treatment approaches including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • implants e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • anti-inflammatory and/or antiproliferative treatment combination with anti-inflammatory drugs is included. Combination is also possible with antihistamine drug substances, bronchodilatatory drugs, NSAID or antagonists of chemokine receptors.
  • aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atame-stane, exemestane and formestane and, in part-icular, nonsteroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g.
  • AROMASIN Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g. un-der the trademark AFEMA. Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR. Amino glutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark, ORIMETEN.
  • a combination of the invention comprising a chemo-therapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.
  • anti-estrogen as used herein relates to a compound which antagonizes the ef-fect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX.
  • Ralo-xifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX.
  • a combination of the invention comprising a chemotherapeutic agent which is an anti-estrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of in-hibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in US 4,636,505.
  • CASODEX bicalutamide
  • gonadorelin agonist includes, but is not limited to abarelix, goserelin and goserelin acetate.
  • Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX.
  • Abarelix can be formulated, e.g. as disclosed in US 5,843,901.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU- 166148 (compound Al in WO99/ 17804).
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN.
  • topoisomerase II inhibitor includes, but is not limited to the an-thracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g. in the form as it is marketed, e.g.
  • Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN.
  • Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS.
  • Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
  • microtubule active compound relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
  • Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R.P.
  • Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN.
  • Discodermolide can be obtained, e.g., as disclosed in US 5,010,099.
  • Epothilone derivatives which are disclosed in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferred are Epothilone A and/or B.
  • alkylating compound includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN.
  • Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds such as sodium butyrate, LDH589 disclosed in WO 02/22577, especially N-hydroxy-3 - [4- [ [(2-hydroxy ethyl) [2-( 1 H-indo 1-3 -yl)ethyl] -amino]methyl] phenyl] -2E-2-propenamide, N-hy droxy-3- [4- [[[2-(2 -methyl- 1 H-indo 1-3 -yl)-ethyl]- amino] methyl]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts thereof, especially the lactate salt.
  • SAHA suberoylanilide hydroxamic acid
  • MS275 MS275
  • FK228 formerly FR9012228
  • trichostatin A compounds disclosed in US 6,552,065, in particular, N-hydroxy-3-[4-[[[2-(2-methyl- lH-indol-3-yl)-ethyl]-amino]-methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.
  • antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5- azacy-ti-dine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine can be administe-red, e.g., in the form as it is marketed, e.g. under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN.
  • compounds targeting/decreasing a protein or lipid kinase activity includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g., a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, e.g.
  • PDGFR platelet-derived growth factor-receptors
  • a N-phenyl-2-pyrimidine-amine derivative e.g. imatinib, SUlOl, SU6668 and GFB-111
  • imatinib h
  • imatinib or nilotinib AMN107
  • PD180970 AG957
  • NSC 680410 PD173955 from ParkeDavis
  • dasatinib BMS-354825
  • PKC protein kinase C
  • Raf family of serine/threonine kinases members of the MEK, SRC, JAK, FAK, PDKl, PKB/Akt, and Ras/MAPK family members
  • CDK cyclin-dependent kinase family
  • examples of further compounds include e.g. UCN-Ol, safmgol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; BEZ235 (a P13K inhibitor) or AT7519 (CDK inhibitor); j) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein- tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin.
  • GLEEVEC imatinib mesylate
  • tyrphostin include imatinib mesylate (GLEEVEC) or tyrphostin.
  • a tyrphostin is preferably a low molecular weight (mw ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- ⁇ [(2,5- dihydroxyphenyl)methyl] amino ⁇ -benzoic acid adamantyl ester; NSC 680410, adaphostin); k) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor t
  • EGF receptor ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound known as CP 358774), WO 96/33980 (e.g.
  • compound ZD 1839 and WO 95/03283 e.g. compound ZM105180
  • trastuzumab Herceptin
  • cetuximab Erbitux
  • Iressa Tarceva
  • OSI-774 CI-1033
  • EKB-569 EKB-569
  • anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g., inhibitors of phosphatase 1, phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes are e.g. retinoic acid, or tocopherol or tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5- alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS.
  • titaniumudronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID.
  • “Pamidronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIA.
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX.
  • “Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL.
  • "Zoledronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune), everolimus (CerticanO), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons, e.g. interferon.
  • inhibitor of Ras oncogenic iso forms e.g. H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl transferase inhibitor” e.g. L-744832, DK8G557 or Rl 15777 (Zarnestra).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g. telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (Velcade) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g. PKC412, TKI258, midostaurin, a staurosporine derivative, SUl 1248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds, and radicicol.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (Herceptin), Trastuzumab-DMl,erbitux, bevacizumab (Avastin), rituximab (Rituxan), PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispe-cif ⁇ c antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • antigenemic compounds includes, for example, Ara-C, a pyrimidine analog, which is the 2-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • Somatostatin receptor antagonists refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230 (pasireotide).
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al, Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).
  • EDG binders refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l,3-dione derivatives, such as PL-I, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
  • S-adenosylmethionine decarboxylase inhibitors includes, but is not limited to the compounds disclosed in US 5,461,076. Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF disclosed in WO 98/35958, e.g. l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g.
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porf ⁇ mer sodium.
  • Angiostatic steroids refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11 — epihydrocotisol, cortexolone, 17-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • angiogenesis such as, e.g., anecortave, triamcinolone, hydrocortisone, 11 — epihydrocotisol, cortexolone, 17-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as e.g. fluocinolone, dexamethasone.
  • “Other chemotherapeutic compounds” include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • biological response modifiers preferably lymphokines or interferons
  • antisense oligonucleotides or oligonucleotide derivatives preferably shRNA or siRNA
  • shRNA or siRNA or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the structure of the active compounds identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications).
  • the compounds of the invention may also be administered simultaneously, separately or sequentially in combination with one or more other suitable active agents selected from the following classes of agents: Anti IL-I agents, e.g: Anakinra; anti cytokine and anti-cytokine receptor agents, e.g. anti IL-6 R Ab, anti IL- 15 Ab, anti IL- 17 Ab, anti IL-12 Ab; B-cell and T-cell modulating drugs, e.g. anti CD20 Ab; CTL4-Ig, disease- modifying anti-rheumatic agents (DMARDs), e.g.
  • DMARDs disease- modifying anti-rheumatic agents
  • methotrexate leflunamide, sulfasalazine; gold salts, penicillamine, hydroxychloroquine and chloroquine, azathioprine, glucocorticoids and non-steroidal antiinflammatories (NSAIDs), e.g. cyclooxygenase inhibitors, selective COX-2 inhibitors, agents which modulate migration of immune cells, e.g. chemokine receptor antagonists, modulators of adhesion molecules, e.g. inhibitors of LFA-I, VLA-4.
  • NSAIDs non-steroidal antiinflammatories
  • the present invention is also in relation to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or Id or its prodrug and pharmaceutically acceptable excipients.
  • the prodrug is selected from a group comprising, esters and hydrates.
  • pro-drug is also meant to include any covalently bonded carries which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Pro-drugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • the excipients are selected from a group comprising, binders, anti-adherents, disintegrants, fillers, diluents, flavors, colors, glidants, lubricants, preservatives, sorbents and sweeteners or combination(s) thereof.
  • the composition is formulated into various dosage forms selected from a group comprising tablet, troches, lozenges, aqueous or oily suspensions, ointment, patch, gel, lotion, dentifrice, capsule, emulsion, creams, spray, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups and elixirs.
  • Dosages of agents of the invention employed in practicing the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for oral administration are of the order of 0.1 to 10 mg/kg.
  • EtOAc Ethylacetate triflic anhydride: trifluromethanesulfonic anhydride
  • Pd(O Ac)2 palladium acetate
  • BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl;
  • LiOH lithium hydroxide
  • NBS N-bromosuccinamide
  • NIS N-iodosuccinimide
  • LiHMDS lithium bis(trimethylsilyl)amide
  • NaHMDS sodium bis(trimethylsilyl)amide
  • KHMDS potassium bis(trimethylsilyl)amide
  • CDCI3 deuterated chloroform
  • HPLC high pressure liquid chromatography or high performance liquid chromatography.
  • Triethylamine is added to a mixture of 5-methoxy-3,4-dihydro-2H-pyrrole (73 g, 0.73 mmol) and 3-oxopentanedioic acid diethyl ester (200 g, 0.99 mmol) at room temperature. The resulting solution is stirred for 5 days after which the reaction mixture is filtered to give 39 g (24% yield) of 7-hydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethyl ester as a white solid.
  • the NMR spectrum of the title compound is according to theory.
  • the reaction mixture is diluted with ethyl acetate (60ml) and filtered.
  • the filtrate is washed with water (100ml) and the aqueous layer is re-extracted with ethyl acetate (30ml).
  • the combined organic extracts are dried (anhydrous Na 2 SO 4 ), concentrated, and the crude product is purified by column chromatography on silica gel (60-120 mesh) using 0.1-0.5% MeOH in chloroform to afford 336 mg (13% yield) of the title compound.
  • reaction mixture is diluted with ethyl acetate (20ml) and washed with saturated aqueous NH 4 Cl solution (25ml), saturated aqueous NaHCOs solution (25ml), and brine (25ml).
  • the combined organic extracts are dried (anhydrous Na 2 SO 4 ) and concentrated.
  • the residual material is purified by column chromatography on silica gel (1% MeOH in CHCI3) to afford the title compound in 36% yield.
  • 6-fluoro-7- (2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid 300 mg, 0.69 mmol
  • Trituration with EtOAc and diethyl ether gives the test compound in 40% yield as a pale yellow solid.
  • Step l Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy)-amide.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 1 and step 5 was performed in a manner similar to what has been described for example 2
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8
  • EDCI 530mg, 0.003mol
  • HOBt 364mg, 0.003mol
  • 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid 200mg, 0.46mmol
  • DMF 2OmL
  • DCM 1OmL
  • Lithiumdiisopropylamide (16.5ml, 32.8 mmol) was added to a stirred solution of 2- fluoro-4-iodoaniline (5.6g, 23.47mmol) in dry THF (4OmL) at -78 0 C under nitrogen atmosphere. This was followed by addition of 7-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2g, 9.38mmol) in dry THF(150mL) and the resulting mixture was stirred first for 30min at -78 0 C and then at RT for the next 5 days. The reaction mixture was concentrated and acidified with IN HCl till the pH was about 2.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 27
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 27
  • EDCI O.lOlmg, 0.53mmol
  • HOBt 0.072mg, 0. 53mmol
  • 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indo lizine-8- carboxylic acid (0.200mg,0.48mmol) in DMF (4mL) and TEA (0.1 ml, 1.44mmol) at RT.
  • the reaction mixture was stirred for 30minutes at RT under nitrogen atmosphere. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (0.072mg, 0.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 27
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 27
  • EDCI (0.138mg, 0.72mmol) and HOBt (0.097mg, 0.72mmol) were added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid (0.200mg,0.48mmol) in DMF (5mL) and TEA (0.13 ml, 0.96mmol) at RT. This was followed by addition O-(2-vinyloxy-ethyl)-hydroxylamine (0.99mg, 0.96mmol), TEA (0.13 ml, 0.96mmol) and the reaction flask was stirred for 5hrs at RT under nitrogen atmosphere.
  • EDCI (0.280mg, 0.00 lmol) and HOBt (0.197mg, O.OOlmmol) were added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylicacid (0.200mg, 0.0005mol) in DMF (5mL), TEA (0.005mL) and chloroform (2mL) at O 0 C. The reaction mixture was stirred for 1.30hrs at O 0 C under nitrogen atmosphere.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 27
  • EDCI 0.277mg, 0.00 lmol
  • HOBt 0.200mg, O.OOlmmol
  • 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylicacid (0.200mg, 0.0005mol) in DMF (5mL), TEA (O.lmL) and DCM (2mL) at O 0 C.
  • the reaction mixture was stirred for 1.30hrs at O 0 C under nitrogen atmosphere.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 1 and step 5 was performed in a manner similar to what has been described for example 2
  • reaction mixture was stirred at RT overnight.
  • the reaction mixture was partitioned between ethyl acetate (5OmL) and cold water (5OmL).
  • the organic layer was washed with saturated NaHCOs solution, dried over Na 2 SO 4 and concentrated.
  • Purification by column chromatography (using silica gel, 5% methanol in chloroform as eluant) afford 50mg (19.13% yield) of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide as the required product.
  • TEA 7-hydroxy-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester (13g, 58.27mmol) in distilled POCI3 (32ml, 349mmol) and the reaction mixture was stirred for 16hrs at room temperature under nitrogen atmosphere.
  • POCI3 was distilled, the reaction mixture was poured into an ice cold water and basified with saturated K2CO3 solution to a pH of about 8.5. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated.
  • the concentrate was purified by column chromatography (using silica gel ,75% ethyl acetate in hexane as the eluant) to afford 7.5mg (53.5% yield) of 7-chloro-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester as a yellow solid.
  • NCS (304mg, 0.002282mol) was added to a solution of 7-chloro-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester (500mg, 0.0020 lmol) dissolved in DMF and the reaction mixture was stirred for 18hrs at RT under nitrogen atmosphere. The reaction mixture was extracted with ethylacetate, washed with water and brine solution. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated to afford 400mg (70% yield) of ⁇ J-dichloro-S-oxo-l ⁇ -tetrahydro-indolizine-S-carboxylic acid ethyl ester as the required product.
  • n-Butyl lithium (2ml, 0.003mol) were added dropwise to a stirred solution of diisopropyl amine (0.65ml, 0.005mol) in dry THF (4OmL) over a period of 5mins at - 78 ' C and the reaction mixture was stirred for 30 minutes followed by addition of A- bromo-2-fluoro-phenylamine (462mg, 0.002mol) dissolved in dry THF (5mL) at -78 ' C.
  • reaction mixture was stirred for a further 30 minutes, and was followed by addition of ⁇ -dichloro-S-oxo-l ⁇ -tetrahydro-indolizine-S-carboxylic acid (200mg, O.OOlmol) dissolved in dry THF (1OmL) at -78 ' C with the stirring over a period of 30mins.
  • THF was distilled and the residual mass was acidified by addition of IN HCl, followed by ether with stirring for lOmins.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 1
  • EDCI (286mg, O.OOlmol) and HOBt (202mg, O.OOlmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0005mol) in dry DMF (5mL) at O ' C.
  • the reaction mixture was stirred for 1.30hrs at O 0 C. This was followed by addition of O- methoxy-hydroxylamine hydrochloride (125mg, O.OOlmol), TEA (0.21ml, O.OOlmol) at O ' C.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 1
  • EDCI (286mg, O.OOlmol) and HOBt (202mg, O.O.OOlmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.005mol) in dry DMF (5mL) at O 0 C.
  • the reaction mixture was stirred for 1.30hrs at O 0 C. This was followed by addition of NH 4 Cl (80mg, O.OOlmol), followed by TEA (0.2ml, O.OOlmol) at O ' C.
  • the reaction mixture was stirred for 16hrs at RT.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 1
  • reaction mixture was stirred for 18hrs at RT under nitrogen atmosphere.
  • the reaction mixture was partitioned between EtOAc and water.
  • the organic layer was washed with water, saturated NaHCO 3 solution and brine solution, dried over anhydrous.Na2SO4, concentrated and the crude product was recrystallised using methanol to afford 52g (23.6% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6- chloro-S-oxo-l ⁇ -tetrahydro-indolizine-S-carboxylic acid ethoxy-amide as the required product.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 1 Step: 5
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 1
  • n-Butyl lithium (20ml, 0.032mol) was added drop wise for 5mins to a stirred solution of diisopropyl amine (4.5ml, 0.032mol) in dry THF (5mL) at -78 ' C and the reaction mixture was stirred for 30 minutes. This was followed by the addition of 2-fluoro-4- iodo-phenylamine (5.75g, 0.002mol) dissolved in dry THF (1OmL) at -78 ' C.
  • reaction mixture was stirred for a further 30 minutes and this was followed by addition of ⁇ -dichloro-S-oxo-l ⁇ -tetrahydro-indolizine-S-carboxylic acid (2g, 0.008mol) dissolved in dry THF (13OmL) at -78'C with stirring over a period of 30mins. The stirring was continued for a further 2 days at RT under nitrogen atmosphere. THF was distilled and the residual reaction mixture was acidified by addition of IN HCl.
  • reaction mixture was stirred for 16hrs at RT under nitrogen atmosphere.
  • the reaction mixture was partitioned between EtOAc and water.
  • the organic layer was washed with water, saturated NH 4 Cl, saturated NaHCO 3 solution and brine solution, dried over anhydrous Na 2 SO 4 , concentrated and the concentrate was washed with methanol to afford 55mg (24% yield) of 6-chloro-7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide as the required product.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
  • reaction mixture was stirred for 16hrs at RT under nitrogen atmosphere.
  • the reaction mixture was partitioned between EtOAc and water.
  • the organic layer was washed with water, saturated NaHCOs solution and brine solution, dried over anhydrous Na 2 SO 4 , concentrated and the concentrate was washed with methanol to afford 105mg (48% yield) of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5- oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide as the required product.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
  • EDCI 256mg, 0.001 mo 1
  • HOBt 181mg, 0.001 mo 1
  • 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid 200mg, 0.000446mol
  • dry DMF 5mL
  • O ' C dry DMF
  • the reaction mixture was stirred for 1.30hrs at O 0 C under nitrogen atmosphere. This was followed by addition of O-ethyl-hydroxylamine hydrochloride (130mg, O.OOlmol), TEA (0.2ml, O.OOlmol) at O ' C.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
  • EDCI 256mg, O.OOlmol
  • HOBt 180mg, O.OOlmol
  • 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid 200mg, 0.0004mol
  • dry DMF 5mL
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8 Step: 4
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 47
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8
  • 2-Fluoro-phenylamine (2g, 0.018mol) were added to a solution of selectfluor reagent (5.9g, 0.017mol) and KSCN (1.81g, 0.019mol) in acetonitrile and the resulting reaction mass was stirred for 70hrs at RT.
  • the solvent was distilled and the reaction mass was dissolved in water (30OmL), extracted twice with DCM (75mL) and the organic layer was washed with water (10OmL) and brine solution (10OmL).
  • EDCI (227mg, 0.00 lmol) and HOBt (160mg, 0.00 lmol) were added to a stirred solution of 6-fluoro-7-(2-fluoro-4-methylsulfanyl-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (120mg, 0.0003mol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O- cyclopropylmethyl-hydroxylamine hydrochloride (147mg, O.OOlmol) and TEA (120mg, O.OOlmol). The reaction mixture was stirred for 16 hrs at RT.
  • 2,3,4,5,6-Pentafluoro-benzoic acid trifluoromethyl ester (136mg, 0.0005mol) and pyridine (38mg, 0.0005mol) were added to a solution of 7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (170mg, 0.0004mol) in DMF (3mL) and the reaction mixture was stirred for 4hrs at RT. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with NaHCCh, twice with IM HCl solution and brine solution.
  • Acetic acid (63mg, 0.0003mol) and 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, S-tetrahydro-indolizine-S-carboxylic acid hydrazide (135mg, 0.0003mol) were added to a solution of imidazole- 1-carboxy lie acid [2-(tert-butyl-dimethyl-silanyloxy)- ethyl] -amide (91mg, 0.0003mol) in THF (1OmL) and the reaction mixture was stirred for 14hrs at RT.
  • Acetic acid 25mg, 0.0004mol
  • tetra butyl ammonium fluoride 168mg, O.OOO ⁇ mol
  • 7-(4-bromo-2-fluoro-phenylamino)-8- ⁇ 5-[2- (tert-butyl-dimethyl-silanyloxy)-ethylamino]-[l,3,4]oxadiazol-2-yl ⁇ -6-fluoro-2,3- dihydro-lH-indolizin-5-one 250mg, 0.0004mol
  • THF 6mL
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8
  • EDCI (296mg, 0.0015mol) and HOBt (209mg, 0.0015mol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0005mol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O-methyl- hydroxylamine (130mg, 0.002mol) and TEA (156mg, 0.002mol). The reaction mixture was stirred for 19 hrs at RT.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8
  • EDCI (296mg, 0.002mol) and HOBt (209mg, 0.002mol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0005mol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O-ethyl- hydroxylamine (152mg, 0.002mol) and TEA (156mg, 0.002mol). The reaction mixture was stirred for 18 hrs at RT.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8
  • reaction mixture was partitioned between water and ethyl acetate.
  • the organic layer was washed with saturated NaHCOs, saturated NH 4 Cl, and brine solution, dried over Na 2 SO 4 and concentrated to afford HOmg of the crude product which was used in the next step without a further purification.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 54.
  • EDCI (346mg, 0.002mol) and HOBt (244mg, 0.002mol) were added to a stirred solution of 7-(4-bromo-2-methyl-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (230mg, O.OOlmol) in DMF (3mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O- cyclopropylmethyl-hydroxylamine (224mg, 0.002mol) and TEA (183mg, 0.002mol). The reaction mixture was stirred for 24 hrs at RT.
  • reaction mixture was partitioned between water and ethyl acetate.
  • the organic layer was washed with saturated NaHCOs, saturated NH4C1, and brine solution, dried over Na 2 SO 4 and concentrated.
  • the concentrate was dissolved in 5mL of methanol, 25mL of diethyl ether was added into this and the precipitate formed was collected to afford 40mg (14.7% yield) of 7-(4- bromo-2-methyl-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide as the required product.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 56.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8
  • the concentrate was purified by column chromatography (using silica gel , 2-3% methanol in DCM as eluant) to afford 180mg (82.9% yield) of 2- ⁇ l-[6-fiuoro-7-(2-fiuoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carbonyl]-3-hydroxy-azetidin-3-yl ⁇ -piperidine- 1 -carboxylic acid tert-butyl ester (S-isomer) as the required product.
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 11.
  • EDCI (185mg, O.OOlmol) and HOBt (131mg, O.OOlmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (250mg, O.OOlmol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8
  • Step: 5 Synthesis of 2- ⁇ l-[6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carbonyl]-3-hydroxy-azetidin-3-yl ⁇ -piperidine-l- carboxylic acid tert-butyl ester.
  • EDCI 165mg, O.OOlmol
  • HOBt 178mg, O.OOlmol
  • 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid 250mg, O.OOlmol
  • DMF 5mL
  • Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 11.
  • Step: 5 Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-4-fluoro-l,6,7,8-tetrahydro-3H-l,3,5a- triaza-as-indacene-2,5-dione.
  • Step: 7 Synthesis of Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6- fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8 and step 5 was performed in a manner similar to what has been described for example 61
  • reaction mixture was heated to 5O 0 C for 2hrs.
  • the reaction mixture was partitioned between ethylacetate (3x50mL) and water.
  • the organic layer was washed with saturated NH 4 Cl solution, dried over Na 2 SO 4 , concentrated under reduced pressure and the concentrate was purified by column chromatography (using neutral alumina, ethylacetate as eluant) to afford 22mg (8% yield) of N-[7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizin-8-yl]-N,N-dimethyl-amino-sulfonamide as the required product.
  • Steps 1 to 4 were performed in a manner similar to what has been described for example 8
  • step 5 was performed in a manner similar to what has been described for example 61
  • steps 6 to 8 were performed in a manner similar to what has been described for example 62

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Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts. These compounds can act as potential MEK inhibitors in the treatment of hyperproliferative diseases, like cancer and inflammation. The present invention also reveals methods of preparation thereof.

Description

HETEROCYCLIC COMPOUNDS AS MEK INHIBITORS
The invention relates to compounds which are specific inhibitors of kinase activity of MEK. The invention also relates to the use of the compounds, their pro-drugs or pharmaceutically acceptable composition comprising the compound or their prodrug in the management of hyperproliferative diseases like cancer and inflammation.
Hyperproliferative diseases like cancer and inflammation are attracting the scientific community to provide therapeutic benefits. In this regard efforts have been made to identify and target specific mechanisms which play a role in proliferating the diseases.
Over-activation of mitogen-activated protein (MAP) kinase cascade is known to play an important role in cell proliferation and differentiation. This pathway can be activated when a growth factor binds to its receptor tyrosine kinase. This interaction promotes RAS association with RAF and initiates a phosphorylation cascade through MEK (MAP kinase kinase) to ERK. Inhibition of this pathway is known to be beneficial in hyperproliferative diseases. MEK is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERKl and ERK2. Constitutive activation of MEK/ERK was been found in pancreatic, colon, lung, kidney and ovarian primary tumor samples.
Phosphorylation of MEK appears to increase its affinity and its catalytic activity toward ERK as well as is affinity for ATP. This invention describes compounds that inhibit MEK activity by modulation of ATP binding, association of MEK with ERK by mechanisms that are competitive, and/or allosteric and/or uncompetitive.
Activation of MEK has been demonstrated in many models of disease models thus suggesting that inhibition of MEK could have potential therapeutic benefit in various diseases such as • Pain: Evidence of Efficacy in Pain Models (J. Neurosci. 22:478, 2002; Acta Pharmacol Sin. 26:789 2005; Expert Opin Ther Targets. 9:699, 2005; MoI. Pain. 2:2, 2006)
• Stroke: Evidence of Efficacy in Stroke Models Significant Neuroprotection against Ischemic Brain Injury by Inhibition of the MEK (J. Pharmacol. Exp. Ther. 304:172, 2003; Brain Res. 996:55, 2004)
• Diabetes: Evidence In Diabetic Complications. (Am. J. Physiol. Renal.286, F120 2004)
• Inflammation: Evidence of Efficacy in Inflammation Models. (Biochem Biophy. Res. Com. 268:647. 2000)
• Arthritis Evidence of efficacy in experimental osteoarthritis. (Arthritis & (J. Clin. Invest. 116:163. 2006)
Inhibition of MEK has been shown to have potential therapeutic benefit in several studies.
Thus, as a first embodiment, the invention provides a compound of formula I
Figure imgf000003_0001
and pharmaceutically acceptable salts thereof, wherein
X represents Ci-3-alkylene, -N(R6)-, -O-, or -S(O)P-;
R1 represents aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said rings are optionally substituted by one or more groups independently selected from List 1;
R2 represents H, cyano, or the group -Y-R7; R3 and R4 independently represent H, Ci_6-alkyl, Ci_6-haloalkyl, Ci_6-hydroxyalkyl, hydroxyl, Ci_6.alkoxy, amino, Ci_6-alkylamino, diCi_6-alkylamino, or R3 additionally represents monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings are optionally substituted by one or more groups independently selected from List 1;
R5 represents H, halogen, Ci_3-alkyl, Ci_3alkoxy, -SCi_3alkyl, or Ci_3-haloalkyl;
Y represents a group selected from -D-, -E-, -D-E-, or -E-D-;
D represents a group selected from -N(R )-, -CO-,-CO2-, -SO-, -SO2-, CON(R 9\ )0-, CON(R10)-, -N(R1 ^SO2-, -N(R24)SO2NR25-, -SO2N(R12)-, -N(R13)C0-, N(R14)CON(R15)-, -N(R16)C0-, or -C(=NH)N(R17)-;
E represents a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said rings are optionally substituted by one or more groups independently selected from List 1;
R7 represents H, Ci-6-alkyl, C2-6_alkenyl C2-6_alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein R7 when not H is optionally substituted by one to three groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy, C2- C6-alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci-βhaloalkyl, amino, Ci_6alkylamino, di- Ci_6alkylamino, Ci_6acylamino, Ci_6acylCi_6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings may be optionally substituted by one or two groups independently selected from halogen, cyano, hydroxyl, Ci_6.alkoxy, C2-C6- alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci_6-haloalkyl, amino, Ci_6-alkylamino, di- Ci_6-alkylamino, Ci_6-acylamino and C i_6-acylCi_6- alkylamino;
Z is O or N(R18);
List 1 is selected from hydroxyl, cyano, nitro, Ci-6-alkyl, C2-6.alkenyl, C2-6.alkynyl, Cp6- alkoxy, C2-6_alkenyloxy, C2-6_alkynyloxy, halogen, Cp6_alkylcarbonyl, carboxy, Cp6. alkoxycarbonyl, amino, Ci-6.alkylamino, di-Ci-6.alkylamino, Ci-6-alkylaminocarbonyl, di-Cp6. alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6.alkyl)amino, Cp6. alkylsulfonylamino, Ci-6-alkylsulfonyl(Ci-6-alkyl)amino, Ci-6-thioalkyl, Ci-6-alkylsulfinyl, Cp6. alkylsulfanyl, Ci-6.alkylsulfonyl, aminosulfonyl, Ci-6.alkylaminosulfonyl and di-Ci-6- alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci-6_alkoxy, amino, Ci-6.alkylamino, di-Crβ- alkylamino or cyano;
R26 represents H, Ci_6-alkyl, Ci_6-haloalkyl, Ci_6-hydroxyalkyl, hydroxyl, Ci_6.alkoxy, amino, Ci_6-alkylamino, or diCi_6-alkylamino;
R6, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 R18, R24, and R25 are independently H or Cj-e-alkyl;
m and n are independently 0, 1, 2, or 3; and m + n = 2 or 3;
p is 0, 1, or 2; and wherein
Alkyl or alkylene means a straight chain, branched and/or cyclic hydrocarbon from 1 to 20 carbon atoms. Alkyl moieties having from 1 to 5 carbons are referred to as "lower alkyl" and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, and isobutyl.
Cycloalkyl or cycloalkylene represents a 3-14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic or one of the bicyclic rings is saturated or partially unsaturated and may optionally further comprise a -C(O)- ring member, and the other ring may be aromatic, saturated or partially unsaturated and may include one to three ring members selected from -C(=O), -N(R20)q-, -O- and S(O)r where R20 is H or Ci_6-alkyl, q is 0-1 and r is 0-2;
Aryl or arylene represents a 6-14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic or one of the bicyclic rings is aromatic and the other ring may be aromatic, saturated or partially unsaturated and may include one to three ring members selected from -C(O), -N(R19)q-, -O- and S(O)r where R19 is H or Ci_6-alkyl, q is 0-1 and r is 0-2; Heteroaryl or heteroarylene represents a 5-14 membered monocyclic or bicyclic ring, wherein the monocyclic or one of the bicyclic rings is an aromatic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, and the other ring may be aromatic, saturated or partially unsaturated, and may include one to three ring members selected from -C(O), -N(R21)q-, -O- and S(O)r where R21 is H or Ci_6-alkyl, q is 0-1 and r is 0- 2; and
Heterocycloalkyl or heterocycloalkylene represents a 3-14 membered monocyclic or bicyclic ring, wherein the monocyclic or one of the bicyclic rings is a saturated or partially unsaturated group comprising one or two ring members selected from - N(R22)-, -O- and -S(O)1- and may optionally further comprise a -C(O)- ring member, and the other ring may be aromatic, saturated or partially unsaturated, and may include one to three ring members selected from -C(=O), -N(R23)q-, -O- and S(O)r where R22 or R23 is H or Ci_6-alkyl, q is 0-1 and r is 0-2.
The following specific embodiments of the invention according to formula (I) may be incorporated into the definition of formula (I) and combined in any number of suitable ways.
In one embodiment, X represents -N(H)-.
In another embodiment, R1 represents optionally substituted phenyl.
In another embodiment, optional substitution on R1 is represented by one to three groups independently selected from halogen, e.g. fluoro, bromo or iodo, Ci_6-alkyl, e.g. ethyl, C2-6-alkynyl, e.g. ethynyl, Ci_6-haloalkyl, e. g trifluoromethyl and Ci_6-thioalkyl, e.g. thiomethyl.
In another embodiment, R1 is represented by phenyl substituted in the 2-, 4- and optionally 6- positions, suitably the 2- and 4- positions. In a further embodiment, R1 is represented by phenyl substituted by 2-fluoro and 4-bromo, or, 4-iodo-2-fluorophenyl, or any combination of 2- and 4- substititutuions of iodo, trifluoromethyl, thiomethyl, ethynyl or ethyl. In another embodiment, -D- represents a group selected from -C(O)-,-CO2-, C(O)N(H)O-, -C(0)N(Ci_6-alkyl)0-, -C(O)N(H)- and -C(O)N(C i-e-alkyl)-.
In another embodiment, -E- represents a 5-membered heteroarylene or 5-membered heterocycloalkylene. In a further embodiment, E represents a ring selected from;
Figure imgf000007_0001
Figure imgf000007_0002
In another embodiment, where Y represents -D-E-, -D- may represent -C (O) N (H)- and -E- may represent optionally substituted cycloalkyl, e.g. cyclopentyl or optionally substituted heteroaryl, e.g. thiazole.
In another embodiment, where Y represents -E-D-, -E- may represent optionally substituted heteroaryl, e.g. oxadiazole and -D- may represent -C(O)N(H)-
In another embodiment, Y represents the groups -D- or -E-.
In another embodiment, R7 represents H, d-β-alkyl, e.g. methyl or ethyl, substituted Ci- 6-alkyl, e.g. by one to three, in another embodiment one to two, groups selected from hydroxyl, including di-hydroxyl, Ci_6-alkoxy, e.g. methoxy, C2-C6-alkenyloxy, e.g. ethenyloxy, di-Ci_6-alkylamino, e.g. dimethylamino, Ci_6-acylamino, e.g. acetylamino, and optionally substituted monocyclic cycloalkyl, e.g. cyclopropyl.
In another embodiment, R7 represents H, methyl, ethyl, cyclopropylmethyl, 2- hydroxy ethyl, 2-ethenyloxy ethyl, 3-hydroxypropyl, 2-methoxy ethyl, acetylaminomethyl, 2-dimethylamino ethyl or 2,3-dihydroxypropyl.
In another embodiment, R2 represents -CO2H, COH, -CO2Et, C(O)N(H or CH3)OR7a, where R7a represents methyl, ethyl, cyclopropylmethyl, 2-ethenyloxyethyl, 2- hydroxyethyl and 2,3-dihydroxypropyl, -C(O)N(H or CH3)R711, where R7b represents H, methyl, ethyl, cyclopropylmethyl, 2-methoxy ethyl, 2-hydroxy ethyl, 3- hydroxypropyl, acetylamino methyl, 2-dimethylaminoethyl, cyclopentyl or 2-thiazolyl, or R2 represents oxadiazolylamino.
In another embodiment, the present invention includes compounds of formula I where R2 represents CONHOR7a where R7a represents cyclopropylmethyl, or 2-hydroxyethyl.
In another embodiment, m and n are both 1 or one of m and n is 1 and the other is 2.
In another embodiment, R3 and R4 represent H.
In another embodiment, R5 represents H, halogen, e.g. fluoro or chloro, Ci_3alkoxy, e.g., methoxy, or ethoxy, -SCi_3alkyl, e.g., SCH3, or Ci_3alkyl, e.g. methyl or ethyl. In a further embodiment, R5 is fluoro. In a further embodiment, R5 is methyl.
In another embodiment, Z represents O.
In another embodiment, aryl or arylene represent an optionally substituted phenyl or phenylene, respectively.
In another embodiment, cycloalkyl or cycloalkylene represent an optionally substituted 3-7 membered saturated monocyclic carbocyclic ring, e.g. cyclopropyl or cyclopentyl.
In another embodiment, heteroaryl or heteroarylene represent an optionally substituted 5-6 membered monocyclic aromatic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, e.g. tetrazolyl, thiazolyl or oxadiazolyl.
In another embodiment, heterocycloalkyl or heterocycloalkylene represent an optionally substituted 5-6 membered saturated monocyclic ring comprising one or two ring members selected from -N(R22)-, -O- and -S(O)1-.
In still another embodiment of the present invention, the compound forms a pharmaceutically acceptable salt, selected from a group comprising acid addition salts and base addition salts. In another embodiment, the present invention includes a pharmaceutical composition comprising a compound of formula I or Id and a pharmaceutically acceptable carrier or excipient. In another embodiment, the present invention includes a pharmaceutical composition comprising a compound of formula I or Id in combination with a second active agent, and a pharmaceutically acceptable carrier or excipient.
In another embodiment, the present invention includes compounds of formula Id:
Figure imgf000009_0001
and salts thereof, where
Rd1 represents H, halogen, Ci_3_alkyl, or Ci_3_haloalkyl;
Rd2 represents H, cyano, or the group -Y-Rd5;
Rd3 and Rd4 independently represent hydroxyl, cyano, nitro, Ci-6.alkyl, C2-6-alkenyl, C2-e- alkynyl, d-6-alkoxy, C2-6.alkenyloxy, C2-6.alkynyloxy, halogen, d-6-alkylcarbonyl, carboxy, Ci-6_alkoxycarbonyl, amino, Ci-6-alkylamino, di-Ci-6-alkylamino, Ci-6-alkylaminocarbonyl, di- Ci-6-alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6-alkyl)amino, Cp6. alkylsulfonylamino, Ci-6-alkylsulfonyl(Ci-6.alkyl)amino, Ci-6-thioalkyl, Ci-6-alkylsulfmyl, Ci-&. alkylsulfanyl, Ci-6.alkylsulfonyl, aminosulfonyl, Ci-6.alkylaminosulfonyl and di-Crβ- alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci-6.alkoxy, amino, Ci-6-alkylamino, di-Ci-6. alkylamino or cyano;
Y represents a group selected from -D-, -E-, -D-E-, or -E-D-; D represents a group selected from -N(Rd8)-, -CO-,-CO2-, -SO-, -SO2-, CON(Rd9)O-, - CON(Rd10)-, -N(Rd1 ^SO2-, -N(Rd12)So2NRd13-, -SO2N(Rd14)-, -N(Rd15)CO-, - N(Rd16)CON(Rd17)-, -N(Rd18)CO-, or -C(=NH)N(Rd19)-;
E represents a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said rings are optionally substituted by one or more groups independently selected from List 1 as defined herein;
Rd5 represents H, Ci-6-alkyl, C2-6_alkenyl C2-6-alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein Rd5 when not H is optionally substituted by one to three groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy, C2-C6-alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci-βhaloalkyl, amino, Ci_6alkylamino, di-Ci_6alkylamino, Ci_6acylamino, Ci_6acylCi_6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings may be optionally substituted by one or two groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy, C2-C6- alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci_6-haloalkyl, amino, Ci_6-alkylamino, di- Ci_6-alkylamino, Ci_6-acylamino and C i_6-acylCi_6- alkylamino;
Rd6 and Rd7 independently represent hydroxyl, cyano, nitro, Ci-6-alkyl, C2-6.alkenyl, C2-6. alkynyl, d-6-alkoxy, C2-6_alkenyloxy, C2-6_alkynyloxy, halogen, Ci-6.alkylcarbonyl, carboxy, Ci-6_alkoxycarbonyl, amino, Ci-6.alkylamino, di-Ci-6.alkylamino, Ci-6-alkylaminocarbonyl, di- Ci-6-alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6.alkyl)amino, Cp6. alkylsulfonylamino, Ci-6-alkylsulfonyl(Ci-6-alkyl)amino, Ci-6-thioalkyl, Ci-6-alkylsulfinyl, Cp6. alkylsulfanyl, Ci-6.alkylsulfonyl, aminosulfonyl, Ci-6.alkylaminosulfonyl and di-Crβ- alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci-6_alkoxy, amino, Ci-6.alkylamino, di-Crβ- alkylamino or cyano;
j and g independently represent O, 1, 2, or 3; and
Rd8, Rd9, Rd10, Rd11, Rd12, Rd13, Rd14, Rd15, Rd16, Rd17, Rd18, and Rd19 are independently H or Ci_6-alkyl. In an embodiment, j and g are independently 0, 1, 2, or 3, and j + g = 2, 3, or 4. In another embodiment, j is 0, 1, or 2, and g is 1, 2, or 3. In a further embodiment, j is 0, and g is 0, 1, or 2.
With reference to formulas (I) and (Id), alkyl, alkenyl, alkynyl, and alkoxy groups, containing the requisite number of carbon atoms, can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, i-butoxy, sec-butoxy and t-butoxy.
"Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.
Ci-6-haloalkyl refers to an alkyl group substituted by up to seven halogen groups, e.g. fluoro groups. For example, where the substituent is fluoro, common haloalkyl groups are trifluoroalkyl, 2, 2, 2-trifluoroethyl or 2, 2, 2, 1, 1-pentafluoroethyl groups.
The term "alkenyl" refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon double bond. The term "C2-C6-alkenyl" refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon double bond.
The term "alkynyl" refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond. The term "C2-C6-alkynyl" refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon triple bond.
The term "alkoxy" refers to a group in which an alkyl group is attached to oxygen, wherein alkyl is as previously defined.
It is to be understood that the terminology C (O) refers to a -C=O group, whether it be ketone, aldehyde or acid or acid derivative. Similarly, S (O) refers to a -S=O group. Examples of cycloalkyl groups as defined in formula (I) include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Examples of aryl groups as defined in formula (I) include phenyl, naphthyl, anthracyl and phenanthryl.
Examples of heterocycloalkyl groups as defined in formula I include [1, 3] dioxolane, [1, 4] dioxane, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, thiomorpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.
Examples of monocyclic heteroaryl groups as defined in formula (I) groups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. Examples of bicyclic heteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl, isoindolyl, indolizinyl, benzamidazolyl, and quinolinyl.
Throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
In still another embodiment of the present invention, the compound is a stereoisomer or a tautomer.
A suitable individual compound of the invention is selected from: 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l, 2, 3, S-tetrahydro-indolizine-S-carboxylic acid ethyl ester;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropyl-methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid dimethyl amide; 7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid methoxyl amide;
7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid amide;
7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid ethoxy amide;
7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid (2-hydroxy ethyl) amide;
7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine 8-carboxylic acid methyl amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-ethyl-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carbaldehyde
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropyl methoxy-amide;
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropyl methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropyl methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2 -vinyl oxy-ethoxy)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethoxy-amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid ethyl ester;
2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid;
2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid-cyclopropyl-methoxyamide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid-(2-vinyloxy-ethoxy)-amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid methoxy amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid ethoxy amide;
7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetyrahydro-indolizine-8- carboxylic acid (2-hydroxyethoxy)amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-propyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-methoxy-ethyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-acetylamino-ethyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-dimethylamino-ethyl)-amide;
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopentylamide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethylamide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (3-methoxy-propyl)-amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy- amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2,3-dihydroxy-propoxy)-amide; 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid methoxy-amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethoxy-amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2,3-dihydroxy-propoxy)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid thiazol-2-ylamide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (3-hydroxy-propyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid dimethylamide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-methoxy-ethyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-acetylamino-ethyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (pyridin-2-ylmethyl)-amide;
6-Fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid;
6-Fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide; 6-Fluoro-7-(2-fluoro-4-methylsulfanyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-[5-(2-hydroxy-ethylamino)- [l,3,4]oxadiazol-2-yl]-2,3-dihydro-lH-indolizin-5-one; 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(4-Bromo-2-methyl-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
7-(4-Bromo-2-methyl-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide;
7-(4-Bromo-2-methyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid;
7-(4-Bromo-2-methyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-8-(3-hydroxy-3-piperidin-2-yl-azetidine-l- carbonyl)-2,3-dihydro-lH-indolizin-5-one hydrochloride;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(3-hydroxy-3-piperidin-2-yl-azetidine- l-carbonyl)-2,3-dihydro-lH-indolizin-5-one;
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-8-(3-hydroxy-3-piperidin-2-yl-azetidine-l- carbonyl)-2,3-dihydro-lH-indolizin-5-one;
Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro -indo lizin- 8 -y 1] -amide ;
N-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8- yl]-N,N-dimethyl-amino-sulfonamide;
2,3-Dihydroxy-propane-amino-sulfonicacid-[7-(4-bromo-2-fluoro-phenylamino)-6- fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; l-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8- ylsulfamoyl] -pyrrolidine-2-carboxylic acid;
2-Hydroxymethyl-pyrrolidine- 1 -sulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6- fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-but-3-enyl)-2,3-dihydro-
1 H-indo lizin-5 -one; 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-allyl)-2,3-dihydro-lH- indolizin-5-one;
7-(4-Bromo-2-fluoro-phenylamino)-8-(2,3-dihydroxy-propionyl)-6-fluoro-2,3-dihydro-
1 H-indo lizin-5 -one;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(2-hydroxy-acetyl)-2,3-dihydro-lH- indolizin-5-one;
7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethyl ester;
7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide;
7-(2-Fluoro-4-methoxy-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carbaldehyde oxime;
7-(4-Bromo-2-fluoro-phenylamino)-8-(3-hydroxy-3-pyridin-2-yl-azetidine-l-carbonyl)-
2,3-dihydro-lH-indolizin-5-one;
7-(4-Bromo-2-fluoro-phenylamino)-8-(3-hydroxy-azetidine-l-carbonyl)-2,3-dihydro-
1 H-indo lizin-5 -one;
3-(4-Bromo-2-fluoro-phenyl)- 1 -methanesulfonyl- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a-triaza- as-indacene-2,5-dione;
Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l, 2,3,5- tetrahydro -indo lizin- 8 -y 1] -amide ;
N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-4- fluoro-benzenesulfonamide;
[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-carbamic acid tert-butyl ester;
Cyclohexanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l, 2,3,5- tetrahydro -indo lizin- 8 -y 1] -amide ;
N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-4- trifluoromethyl-benzenesulfonamide; N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-N,N- dimethylaminosulfonamide;
5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3- dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid;
7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid ethyl ester;
7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid cyclopropylmethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid cyclobutylmethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid (3-hydroxy-2-methyl-propoxy)-amide;
1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [6-fluoro-7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; 1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; 1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2,3-dihydroxy-propoxy)-amide;
7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8- carboxylic acid cyclopropyl methoxy amide;
7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l , 2,3, 5-tetrahydro-indolizine-8- carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid cyclobutylmethoxy-amide;
1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; and Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- l,2,3,5-tetrahydro-indolizin-8-yl]-amide, or a pharmaceutically acceptable salt thereof. Many of the compounds represented by formula I and Id are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, , propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p- hydroxybenzoic acid, l-hydroxynaphthalene-2-carboxylic acid or 3- hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I and Id by known salt-forming procedures.
Compounds of formula I and Id which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula I and Id by known salt-forming procedures.
In those compounds where there is an asymmetric carbon atom the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures. The present invention embraces both individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof.
The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) and (Id) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Isotopically-labeled compounds of formula (I) and (Id) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations Sections using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
The invention provides, in another aspect, a process for preparing a compound of formula (I) and (Id). The schemes detailed below show general schemes for synthesizing compounds of formula (I) and (Id). It is recognized that the compounds corresponding to the Roman numerals in the schemes do not correspond to the Roman numerals of claimed compounds.
Scheme 1.
Figure imgf000022_0001
Compounds of formula II may be prepared using published methods described in J. Org. Chem., 1995, 60, 2912 and Tetrahedron, 2002, 58, 2821,
Compounds of formula II may be converted into compounds of formula III by reaction with a halogenating agent such as phosphorus oxybromide, neat or in a suitable solvent such as toluene, at temperatures ranging from room temperature to 14O0C.
Alternatively, compounds of formula II may be reacted with nonafluorobutane sulphonyl fluoride in the presence of a base such as diisopropyl ethylamine and a catalyst, such as N,N-dimethyl-4-aminopyridine, in a solvent such as dichloro methane, at room temperature, or with N-phenyltrifluoromethanesulfonimide in the presence of a base, such as diisopropylethyl amine, in a suitable solvent, such as 1,2- dimethoxy ethane, at temperatures ranging from room temperature to the refluxing temperature of the solvent. In addition, compounds of formula II may be treated with trifluromethanesulphonic acid anhydride in the presence of base, such as pyridine, in a solvent, such as dichloromethane, at temperatures ranging from -2O0C to ambient temperature.
Compounds of formula IV may be obtained from compounds of formula III by reaction with appropriate anilines or phenols or thiophenols, using Buchwald-Hartwig C-N/S/O coupling conditions. The Buchwald-Hartwig reactions may be performed in presence of a catalyst such as tris(dibenzylidineacetone)dipalladium (0) or palladium acetate, a base such as potassium phosphate, sodium tert-butoxide, 1.8-diazobicyclo[5.4.1]undec- 7-ene or cesium carbonate, a ligand such as 9,9'-dimethyl-4,5-bis(diphenylphosphino)- xanthene, 2,2'-bis(diphenylphosphino)-l-l '-binaphthyl, 2-dicyclohexylphosphino-2'- (N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',6'-(dimethoxy)biphenyl or tributylphosphine, in a suitable solvent such as toluene, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or under microwave irradiation at a temperature ranging from 7O0C to 15O0C.
Compounds of formula V can be obtained from compounds of formula IV by reaction with a base such as sodium hydroxide in a protic solvent such as ethanol or methanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent.
Compounds of formula V can be treated with a functionalized hydroxylamine or an amine and a suitable coupling agent, such as O-(7-azabenzo-triazol-l-yl)-N,N,N',N'- tetra-methyluronium hexafluorophosphate, N-(3 -dimethylaminopropyl)-N ' - ethylcarbodimidime hydrochloride or N,N-dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole, with a suitable base such as diisopropylethylamine or triethylamine, in an aprotic solvent such as tetrahydrofuran, N,N-dimethylformamide, or dichloromethane, at temperatures ranging from O0C to room temperature, to obtain the compounds of formula VI. Alternatively, compounds of formula VI can be obtained directly from compounds of formula IV by reaction with an amine or hydroxylamine in the presence of a Lewis acid such as trimethyl aluminum, in a solvent such as dichloromethane, at temperatures ranging from room temperature to the refluxing temperature of the solvent. Scheme 2 Scheme 2.
Figure imgf000024_0001
Compounds of formula III can be converted to compounds of formula VII by electrophilic halogenation using reagents such as [l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)] in a suitable solvent, such as acetonitrile, at temperatures ranging from room temperature to 7O0C.
Compounds of formula VII can be converted into compounds of formula VIII using the conditions as described for the preparation of compounds of formula IV (scheme 1). Compounds of formula VIII can be converted into compounds of formula IX using the conditions as described for the preparation of compounds of formula V (scheme 1). Compounds of formula IX can be converted into compounds of formula X using the conditions as described for the preparation of compounds of formula VI (scheme 1). Alternatively, compounds of formula X can be obtained directly from compounds of formula VIII by reaction with an amine or a hydroxylamine using the conditions as described for the preparation of compounds of formula VI (scheme 1)
Scheme 3.
Figure imgf000025_0001
Compounds of formula XI may be prepared from compounds of formula II by reacting the latter with a base such as NaH and an alkylating agent such as methyl iodide or a halogenating agents such as deoxyfluor, NCS, NBS, NIS, in a suitable solvent such as THF or DMF, at temperatures ranging from room temperature to 10O0C. Compounds of formula XI can be transformed to compounds of formula VII using the same conditions as described for the preparation of compounds of formula II (scheme 1).
Scheme 4.
Figure imgf000026_0001
Compounds of formula XII can be obtained from compounds of formula VII by reaction with a base such as sodium or lithium hydroxide in a protic solvent such as ethanol or methanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent.
Compounds of formula XII can then be converted into compounds of formula IX using an SNAR reaction. The latter is carried out in a suitable solvent such as THF, using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures, typically ranging from -780C to room temperature.
Compounds of formula IX can be converted into compounds of formula X using the same conditions as described for the preparation of compounds of formula VI (scheme
Scheme 5.
Figure imgf000027_0001
Compounds of formula IX can be converted into compounds of formula XIII with hydrazine by standard coupling procedures using reagents like EDCI or PyBOP in the presence of HOBt in a suitable organic solvent such as DMF, THF or dichloromethane.
Compounds of formula XIII can then be converted into compounds of formula XIV using either carbonyldiimidazole, phosgene, or a phosgene equivalent, in a suitable organic solvent such as DMF, toluene, or dichloromethane.
Compounds of formula XV are accessible from compounds of formula XIV by the addition of an appropriate amine followed by re-cyclization of the intermediate acyl hydrazide using triphenylphosphine, triethylamine, and CC14 in dichcloromethane.
Scheme 6.
Figure imgf000028_0001
Aldehydes and ketones of formula XVI can be prepared from acids of formula IX using the standard methods, such as converting the acids into corresponding Weinreb amide, followed by treatment with appropriate organo -metallic reagents.
Oxadiazoles of formula XVII can be prepared by acylating the respective amidoxime, followed by dehydrative cyclization.
Acyl azides of formula XVIII can be prepared from compounds of the general formula IX via the acid halide, for example the acid chloride using standard conditions. The formula XVIII compounds can then be transformed via the Curtius rearrangement to give compounds of the general formula XIX.
Following standard methodology, acids of formula IX are converted to the corresponding amides, which are then dehydrated to give the corresponding nitriles of formula XX. Formula XX compounds can be treated with trimethylsilyl azide or NaN3 in a suitable aprotic solvent such as N, N-dimethylformamide, at temperatures ranging from room temperature to 1000C to yield compounds of formula XXI.
The inhibitory properties of compounds of formula I and Id may be demonstrated using the following test procedures:
A BRAF-MEK-ERK cascade assay is used to evaluate the effects of these compounds as inhibitors of the MAP kinase pathway. An enzymatic cascade assay is set up using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557), human full length unactive MEKl kinase (Cat No. 14-706) and human full length unactive MAP Kinase 2/ERK2 (Cat No. 14-536) enzymes procured from Upstate. TR-FRET (Time resolved fluorescence resonance energy transfer) detection technology is used for the read out. The assay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgC12 , 1 mM DTT, 0.01 % Tween 20, 0.1 nM activated BRAF, 2 nM unactive MEKl,10 nM unactive ERK2, 100 μM ATP and 500 nM long chain biotin-peptide substrate (LCB- FFKNIVTPRTPPP) in a 384 well format. The kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu- labeled phospho- serine/threonine antibody (Cat. No.AD0176-Perkin Elmer), 20 nM SA-APC (Cat No. CR130-100-Perkin Elmer) is added. The TR-FRET signal (Excitation at 340 nm, Emission at 615 nm and 665 nm) is read with 50 μs delay time on a Victor3 V fluorimeter. The data is calculated using the ratio of readings at 665nm to 615 nm. The final concentration of DMSO is 2.5 % in the assay. Compounds are screened at 10 μM concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
Each individual IC50 is determined using a 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response (variable slope).
An in-vitro MAP kinase assay is set up using activated MAP kinase 2/ERK2 (Cat. No.14-550) obtained from Upstate. TR-FRET detection technology is used for the read out. The assay buffer solution contains 50 rnM Tris pH 7.5, 10 rnM MgC12 , 1 rnM DTT, 0.01 % Tween 20, 1 nM activated ERK2, 100 μM ATP and 500 nM long chain biotin- peptide substrate (LCB- FFKNI VTPRTPPP) in a 384 well format. The kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu- labeled phospho-serine/threonine antibody (Cat.No. AD0176-Perkin Elmer), 20 nM SA-APC (Cat. No. CR130-100-Perkin Elmer) is added. The TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read with 50 μs delay time on Victor3 V fluorimeter. The data is calculated using the ratio of readings at 665nm to 615 nm. The final concentration of DMSO is 2.5 % in the assay. Compounds are screened at 10 μM concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
The radioactive filter binding assay is standardized using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557) and kinase dead MEKl (K97R) ( Cat No. 14- 737) procured from Upstate. The incorporation of 32P into MEKl (K97R) by BRAF (V599E) is measured with final assay buffer conditions of 50 mM Tris pH 7.5, 10 mM MgC12 , 1 mM DTT, 100 mM sucrose, 100 μM sodium orthovanadate,5 μM ATP and 2 μCi [ γ 32P] ATP and 500 mg MEKl Kinase dead substrate. The enzymatic reaction is stopped after 120 minutes with 8N HCl (hydrochloric acid) and 1 mM ATP. The solution is spotted on P81 filter paper and washed 4 times with 0.75 % orthophosphoric acid and lastly with acetone. The dried P81 filter papers are read in a Micro-beta Trilux scintillation counter. The final concentration of DMSO is 1 % in the assay. Compounds are screened at 10 μM concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
These assays described above are fully detailed in Han, Shulin, et. al., Bioorganic & Medicinal Chemistry Letters (2005) 15, 5467-5473, and in Yeh, et. al., Clin Cancer Res (2007) 13 (5), 1576-1583.
The cell viability assay in A375 cells is set up in a 96-well plate format using XTT. XTT is a yellow tetrazolium salt that is cleaved to an orange formazan dye by the mitochondria of metabolically active cells. The procedure allows for rapid determination in a microtitre plate, to give reproducible and sensitive results.
A375 cells are grown in DMEM media containing 10% FBS and ImM sodium pyruvate. Cells are trypsinized and seeded at 1000 cells/well. After allowing the cells to adhere overnight, compound is added to the wells at the following final concentrations: 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001, and 0.0001 μM. The assay is set up in triplicates for each concentration. DMSO concentrations are kept at 0.5% /well. Three days after compound addition, the XTT assay is performed. Wells are washed once with PBS. 100 μL of DMEM media without phenol red or FBS is added to each well. A working solution of XTT containing lmg/ml XTT and 100 μL of PMS (stock concentration 0.383 mg/ml) per 5ml is prepared. 50 μL of the working solution of XTT is added to each well. Absorbance of the plate is read at 465nm using a Spectramax 190 (Molecular Devices). The absorbance from wells with media and XTT alone, but without cells is considered the blank and subtracted from readings from all wells.
Percentage viability is calculated considering the blank subtracted value from wells treated with DMSO alone as 100% viable. GI50 values are calculated using Graphpad Prism, using non-linear regression curve fit for sigmoidal dose response (variable slope).
The cell viability assay is further described in Scudiero, et. al., Cancer Research (1988) 48, 4827-4833; Weislow, et. al., J. Natl. Cancer Institute, (1989) 81, 577-586; and Roehm, et. al., J. Immunol.Methods [1991]142:257-265.
The compounds of the present invention are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the Raf/Ras/Mek pathway.
Thus, as a further aspect, the invention relates to a method for treating a disease or condition related to the hyperactivity of MEK, or a disease or condition modulated by the MEK cascade, comprising administration of an effective therapeutic amount of a compound of formula (I) or (Id) or a pharmaceutically acceptable salt thereof.
As a further aspect, the invention relates to a method for treating proliferative diseases, such as cancer, comprising administration of an effective amount of a compound of formula (I) or (Id) or a pharmaceutically acceptable salt thereof.
Examples of cancers include but are not limited to: angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma; bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, lymphoma, chondromatous hanlartoma, mesothelioma, esophageal squamous cell carcinoma, leiomyosarcoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, vipoma, stomach and small bowel carcinoid tumors, adenocarcinoma, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, villous adenoma, hamartoma, Wilm's tumor [nephroblastoma, leukemia, bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, seminoma, teratoma, embryonal carcinoma, teratocareinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma, osteogenic sarcoma (osteosarcoma), malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxo fibroma, osteoid osteoma and giant cell tumors, osteoma, granuloma, xanthoma, osteitis deformans, meningioma, meningio sarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, meningioma, glioma, endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa- thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, intraepithelial carcinoma, adenocarcinoma, melanoma), vaginal clear cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube carcinoma, acute and chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma, malignant melanoma, basal cell carcinoma, moles, dysplastic nevi, angioma, dermatofibroma, keloids, psoriasis, and neuroblastoma.
The compounds of the present invention may also be useful in the treatment of other diseases or conditions related to the hyperactivity of MEK. Thus, as a further aspect, the invention relates to a method of treatment of a disorder selected from: xenograft (cellos), skin, limb, organ or bone marrow transplant) rejection; osteoarthritis; rheumatoid arthritis; cystic fibrosis; complications of diabetes (including diabetic retinopathy and diabetic nephropathy); hepatomegaly; cardiomegaly; stroke (such as acute focal ischemic stroke and global cerebral ischemia); heart failure; septic shock; asthma; chronic obstructive pulmonary disorder; Alzheimer's disease; and chronic or neuropathic pain.
The term "chronic pain" for purposes of the present invention includes, but is not limited to, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic pain is associated with numerous conditions including, but not limited to, inflammation, and post-operative pain. As used herein, the term "neuropathic pain" is associated with numerous conditions which include, but are not limited to, inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, and nerve injury between the peripheral nervous system and the central nervous system. Compounds of the invention may also be useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV) human papilloma virus (HPV), cytomegalovirus (CMV], and Epstein-Barr virus (EBV). Compounds of the invention may also be useful in the treatment of restenosis, psoriasis, allergic contact dermatitis, autoimmune disease, atherosclerosis and inflammatory bowel diseases, e.g. Crohn's disease and ulcerative colitis.
An MEK inhibitor of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. For example, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from chemotherapy agents, e.g. mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents, e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(l H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.
Such combinations may offer significant advantages, including synergistic activity, in therapy.
A compound of the formula (I) or (Id) may also be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors, such as LBH589; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors, such as RADOOl; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti- angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3, such as PKC412; Hsp90 inhibitors such as 17-AAG (17- allylamino-gelda-namycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino- 17-demethoxy-geldana-mycin, NSC707545), IPI-504, CNFlOlO, CNF2024, CNFlOlO from Conforma Therapeutics and AUY922; temozolomide (TEMODAL); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; PBK inhibitors, such as BEZ235; RAF inhibitors, such as RAF265; EDG binders, antileukemia compounds, ribonucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, antiproliferative anti-bodies or other chemotherapeutic compounds. Further, alternatively or in addition they may be used in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids, hormones, or they may be used as radiosensitizers. Also, in antiinflammatory and/or antiproliferative treatment, combination with anti-inflammatory drugs is included. Combination is also possible with antihistamine drug substances, bronchodilatatory drugs, NSAID or antagonists of chemokine receptors.
The term "aromatase inhibitor" as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atame-stane, exemestane and formestane and, in part-icular, nonsteroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark AROMASIN. Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g. un-der the trademark AFEMA. Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR. Amino glutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark, ORIMETEN. A combination of the invention comprising a chemo-therapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.
The term "anti-estrogen" as used herein relates to a compound which antagonizes the ef-fect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX. Ralo-xifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA. Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent which is an anti-estrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
The term "anti-androgen" as used herein relates to any substance which is capable of in-hibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in US 4,636,505.
The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX. Abarelix can be formulated, e.g. as disclosed in US 5,843,901.
The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU- 166148 (compound Al in WO99/ 17804). Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTOSAR. Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN.
The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the an-thracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS. Teniposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark VM 26-BRISTOL. Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUBICIN. Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
The term "microtubule active compound" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL. Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE. Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R.P. Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN. Discodermolide can be obtained, e.g., as disclosed in US 5,010,099. Also included are Epothilone derivatives which are disclosed in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferred are Epothilone A and/or B.
The term "alkylating compound" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.
The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds such as sodium butyrate, LDH589 disclosed in WO 02/22577, especially N-hydroxy-3 - [4- [ [(2-hydroxy ethyl) [2-( 1 H-indo 1-3 -yl)ethyl] -amino]methyl] phenyl] -2E-2-propenamide, N-hy droxy-3- [4- [[[2-(2 -methyl- 1 H-indo 1-3 -yl)-ethyl]- amino] methyl]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts thereof, especially the lactate salt. It further especially includes suberoylanilide hydroxamic acid (SAHA), MS275, FK228 (formerly FR901228), trichostatin A and compounds disclosed in US 6,552,065, in particular, N-hydroxy-3-[4-[[[2-(2-methyl- lH-indol-3-yl)-ethyl]-amino]-methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.
The term "antineoplastic antimetabolite" includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5- azacy-ti-dine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine can be administe-red, e.g., in the form as it is marketed, e.g. under the trademark XELODA. Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR.
The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN.
The term "compounds targeting/decreasing a protein or lipid kinase activity"; or a "protein or lipid phosphatase activity"; or "further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g., a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SUlOl, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, such as those compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the AxI receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, i.e C-kit receptor tyrosine kinases - (part of the PDGFR family), such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, e.g. imatinib; h) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-AbI kinase) and mutants, such as corn-pounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825) i) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDKl, PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin-dependent kinase family (CDK) and are especially those staurosporine derivatives disclosed in US 5,093,330, e.g. midostaurin; examples of further compounds include e.g. UCN-Ol, safmgol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; BEZ235 (a P13K inhibitor) or AT7519 (CDK inhibitor); j) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein- tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin. A tyrphostin is preferably a low molecular weight (mw<1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- {[(2,5- dihydroxyphenyl)methyl] amino} -benzoic acid adamantyl ester; NSC 680410, adaphostin); k) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound known as CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g. compound ZM105180); e.g. trastuzumab (Herceptin), cetuximab (Erbitux), Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW- 2016, El.1, E2.4, E2.5, E6.2, E6.4, E2.l l, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3- d]pyrimidine derivatives which are disclosed in WO 03/013541; and 1) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF.
Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470. Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g., inhibitors of phosphatase 1, phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative thereof.
Compounds which induce cell differentiation processes are e.g. retinoic acid, or tocopherol or tocotrienol.
The term cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5- alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. "Etridonic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL. "Clodronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS. "Tiludronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID. "Pamidronic acid" can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIA. "Alendronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX. "Ibandronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT. "Risedronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL. "Zoledronic acid" can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA.
The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune), everolimus (CerticanO), CCI-779 and ABT578. The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
The term "biological response modifier" as used herein refers to a lymphokine or interferons, e.g. interferon.
The term "inhibitor of Ras oncogenic iso forms", e.g. H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl transferase inhibitor" e.g. L-744832, DK8G557 or Rl 15777 (Zarnestra).
The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g. telomestatin.
The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (Velcade) and MLN 341.
The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996. The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g. PKC412, TKI258, midostaurin, a staurosporine derivative, SUl 1248 and MLN518.
The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds, and radicicol.
The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin), Trastuzumab-DMl,erbitux, bevacizumab (Avastin), rituximab (Rituxan), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispe-cifϊc antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
For the treatment of acute myeloid leukemia (AML), compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
The term "antileukemic compounds" includes, for example, Ara-C, a pyrimidine analog, which is the 2-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
Somatostatin receptor antagonists as used herein refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230 (pasireotide).
Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al, Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).
The term "EDG binders" as used herein refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l,3-dione derivatives, such as PL-I, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
The term "S-adenosylmethionine decarboxylase inhibitors" as used herein includes, but is not limited to the compounds disclosed in US 5,461,076. Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF disclosed in WO 98/35958, e.g. l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci U S A, Vol. 93, pp. 14765- 14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); in WO 00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly et al., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g. Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGl antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin).
Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porfϊmer sodium.
Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11 — epihydrocotisol, cortexolone, 17-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
Implants containing corticosteroids refers to compounds, such as e.g. fluocinolone, dexamethasone.
"Other chemotherapeutic compounds" include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action. The structure of the active compounds identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).
None of the quotations of references made within the present disclosure is to be understood as an admission that the references cited are prior art that would negatively affect the patentability of the present invention.
The compounds of the invention may also be administered simultaneously, separately or sequentially in combination with one or more other suitable active agents selected from the following classes of agents: Anti IL-I agents, e.g: Anakinra; anti cytokine and anti-cytokine receptor agents, e.g. anti IL-6 R Ab, anti IL- 15 Ab, anti IL- 17 Ab, anti IL-12 Ab; B-cell and T-cell modulating drugs, e.g. anti CD20 Ab; CTL4-Ig, disease- modifying anti-rheumatic agents (DMARDs), e.g. methotrexate, leflunamide, sulfasalazine; gold salts, penicillamine, hydroxychloroquine and chloroquine, azathioprine, glucocorticoids and non-steroidal antiinflammatories (NSAIDs), e.g. cyclooxygenase inhibitors, selective COX-2 inhibitors, agents which modulate migration of immune cells, e.g. chemokine receptor antagonists, modulators of adhesion molecules, e.g. inhibitors of LFA-I, VLA-4.
The present invention is also in relation to a pharmaceutical composition comprising a compound of formula I or Id or its prodrug and pharmaceutically acceptable excipients.
In still another embodiment of the present invention, the prodrug is selected from a group comprising, esters and hydrates.
The term pro-drug is also meant to include any covalently bonded carries which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Pro-drugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. In still another embodiment of the present invention, the excipients are selected from a group comprising, binders, anti-adherents, disintegrants, fillers, diluents, flavors, colors, glidants, lubricants, preservatives, sorbents and sweeteners or combination(s) thereof.
In still another embodiment of the present invention, the composition is formulated into various dosage forms selected from a group comprising tablet, troches, lozenges, aqueous or oily suspensions, ointment, patch, gel, lotion, dentifrice, capsule, emulsion, creams, spray, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups and elixirs.
Dosages of agents of the invention employed in practicing the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for oral administration are of the order of 0.1 to 10 mg/kg.
The invention is further illustrated by the following non-limiting examples, where the following abbreviations are employed:
TEA: Triethylamine
DPPA: Diphenylphosphorylazide
LDA: Lithium diisopropylamide
EDCI : 1 -Ethyl-3 -(3 '-dimethylaminopropyl)carbodiimide
DMAP: 4-Dimethylaminopyridine
HOBt: 1 -Hydroxybenzotriazole
Selectfluor: 1 -Chloromethyl-4-fluoro- 1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
Dess-martin periodinane: 1,1,1 -Triacetoxy- 1 , 1 -dihydro- 1 ,2-benziodoxol-3(lH)-one
DCM: Dichloro methane
THF: Tetrahydrofuran
DMF: Dimethylformamide
DIBAL-H: Diisobutylaluminium hydride EtOH: Ethanol
EtOAc: Ethylacetate triflic anhydride: trifluromethanesulfonic anhydride;
DCM: dichloro methane;
Pd(O Ac)2: palladium acetate;
CS2CO3: cesium carbonate;
BINAP : 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl;
LiOH: lithium hydroxide;
EDCI : 1 -ethyl-3 -(3 ' -dimethylaminopropyl)carbodiimide;
RT: room temperature;
TLC: thin layer chromatography,
NCS: N-chlorosuccinimide,
NBS: N-bromosuccinamide,
NIS: N-iodosuccinimide,
LiHMDS: lithium bis(trimethylsilyl)amide,
LDA: lithium diisopropylamide,
NaHMDS: sodium bis(trimethylsilyl)amide,
KHMDS: potassium bis(trimethylsilyl)amide,
ByBOP: benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,
TMS: trimethylsilyl,
MgCl2 ; magnesium chloride,
TBTU: O-(benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate,
NMR: nuclear magnetic resonance,
DMSO-d6: deuterated dimethyl sulfoxide,
CDCI3: deuterated chloroform,
LC-MS : liquid chromatography- mass spectrometry,
HPLC: high pressure liquid chromatography or high performance liquid chromatography.
The examples provided in the description are only to describe the invention, hence they should not be construed to limit the scope of the invention.
Example 1. Step 1.
Compounds of steps I & II may be prepared using published methods described in J. Org. Chem., 1995, 60, 2912 and Tetrahedron, 2002, 58, 2821,
Synthesis of 5-Methoxy-3, 4-dihydro-2H-pyrrole
Figure imgf000049_0001
Pyrrolidin-2-one (85 g, 1 mol) is added dropwise over a period of 2 hours to a stirred solution of dimethyl sulphate (126 g, 1 mol) under a nitrogen atmosphere. The reaction mixture is stirred for 16 hours at 60° C. The reaction mixture is poured onto ice and saturated potassium carbonate solution, extracted with diethyl ether (2x500ml), washed with brine, and dried (anhydrous sodium sulphate). The organic extracts are removed under reduced pressure at 2O0C to give 73 g of crude 5-methoxy-3,4-dihydro-2H- pyrrole as a light yellow color liquid. This compound is used in the next step without further purification. The NMR spectrum of the title compound is according to theory. 1H NMR (CDCl3, 300 MHZ): δ 3.80 (s, 3H), 3.66 (t, 2H), 2.48 ( t, 2H), 2.08-1.95 (m,2H).
Step 2.
Synthesis of T-Hydroxy-S-oxo-l^^S-tetrahydro-indolizine-δ-carboxylic acid ethyl ester
Figure imgf000049_0002
Triethylamine is added to a mixture of 5-methoxy-3,4-dihydro-2H-pyrrole (73 g, 0.73 mmol) and 3-oxopentanedioic acid diethyl ester (200 g, 0.99 mmol) at room temperature. The resulting solution is stirred for 5 days after which the reaction mixture is filtered to give 39 g (24% yield) of 7-hydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethyl ester as a white solid. The NMR spectrum of the title compound is according to theory. 1H NMR (CDCl3, 300 MHZ): δ 11.4 (s, IH), 5.80 (s, IH), 4.40 (q, 2H), 4.15 (t, 2H), 3.50 (t, 2H), 2.3-2.15 (m, 2H), 1.40 (t, 3H).
Step 3.
Synthesis of 5-Oxo-7-trifluoromethanesulfonyloxy-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethyl ester.
Figure imgf000051_0001
A stirred solution of 7-hydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (60 mg, 0.2 mmol) and triethylamine (30 mg, 0.4 mmol) in 5 ml of dichloromethane is cooled to -78'C. Triflic anhydride (91 mg, 0.32 mmol) is then added dropwise over 20 minutes and the resulting reaction mixture is stirred for 12 hours at ambient temperature with TLC monitoring (100% EtOAc). The reaction mixture is washed with aqueous sodium bicarbonate solution (4ml) and water (4ml). The organic layer is dried over anhydrous Na2SO4, concentrated and the resulting product is purified via column chromatography on silica gel (60-120 mesh) using 15% ethyl acetate in hexane as eluant to afford 40 mg (48% yield) of the title compound. LC-MS purity: 95 %, m/z 356 (M+l).
1H NMR (CDCl3, 300 MHZ): δ 6.15 (s, IH), 4.40 (q, 2H), 4.20 (t, 2H), 3.58 (t, 2H), 2.32-2.2 (m, 2H), 1.40 ( t, 3H).
Step 4.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester
Figure imgf000051_0002
A stirred suspension of 5-oxo-7-trifluoromethanesulfonyloxy-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester (2.3 g, 6.4 mmol), 2-fluoro-4-bromo-aniline (1.25 g, 6.5 mmol), cesium carbonate(3.17 g, 9.7 mmol), BINAP (0.6 g, 0.97 mmol), and Pd(OAc)2 (0.15 g, 0.64 mmol) in toluene (100ml) is heated at 80'C for 16 hours. The reaction is monitored by the TLC (9:1 CHCl3-MeOH v/v). The reaction mixture is diluted with ethyl acetate (60ml) and filtered. The filtrate is washed with water (100ml) and the aqueous layer is re-extracted with ethyl acetate (30ml). The combined organic extracts are dried (anhydrous Na2SO4), concentrated, and the crude product is purified by column chromatography on silica gel (60-120 mesh) using 0.1-0.5% MeOH in chloroform to afford 336 mg (13% yield) of the title compound.
LC-MS purity: 98 %, m/z 395, 397(M+, Br pattern).
1H NMR (DMSO-D6, 300 MHZ): δ 9.48 (s, IH), 7.70 (d, IH), 7.49-7.39 (m, 2H), 5.32
(s, IH), 4.30 (q, 2H), 3.95 (t, 2H), 3.48 (t, 2H), 2.14-2.0 (m, 2H), 1.30 (t, 3H).
Example 2.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid
Figure imgf000052_0001
To the solution of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester (280 mg, 0.71 mmol) in, THF:MeOH (4:1, v/v,
6ml), is added, IN aqueous LiOH solution (2ml). The resulting mixture is stirred for 3 hours at room temperature with TLC monitoring (CHCI3 -MeOH, 8:2). The pH of the reaction mixture is adjusted to 1 with 10% aqueous HCl solution and the resulting precipitate is filtered, washed with water (20ml) and ethyl acetate (10ml) to afford 240 mg (92% yield) of the title compound.
LC-MS purity: 96 %, m/z 367, 369(M+, Br pattern).
1H NMR (DMSO-D6, 300 MHZ): δ 13.40 (s, IH), 9.90 (s, IH) 7.70 (d, IH), 7.45 (s,
2H), 5.35 (s, IH), 3.95 (t, 2H), 3.49 (t, 2H), 2.15-2.0 (m, 2H).
Example 3.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropyl-methoxy-amide
Figure imgf000052_0002
To a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (140 mg, 0.38 mmol) in 10ml of dry DMF are added EDCI (220 mg, 1.14 mmol) and HOBt (160 mg, 1.14 mmol). The reaction mixture is stirred for 30 minutes and then treated with O-cyclopropylmethylhydroxylamine (141 mg, 1.14 mmol) and TEA (232 mg, 1.14 mmol). The resulting reaction mixture is stirred for 16 hours with TLC monitoring (MeOH-CHCl3 2:8, v/v). The reaction mixture is diluted with ethyl acetate (20ml) and washed with saturated aqueous NH4Cl solution (25ml), saturated aqueous NaHCOs solution (25ml), and brine (25ml). The combined organic extracts are dried (anhydrous Na2SO4) and concentrated. The residual material is purified by column chromatography on silica gel (1% MeOH in CHCI3) to afford the title compound in 36% yield.
LC-MS purity: 97%, m/z 436, 438 (M+, Br Pattern).
1H NMR (DMSO-D6, 300 MHZ): δ 11.20 (s, IH), 8.25 (s, IH), 7.65 (d,lH), 7.45-7.3 ( m, 2H), 5.38 (s, IH), 3.91 (t, 2H), 3.72 (d, 2H), 3.25 (t, 2H), 2.15-2.0 (m, 2H), 1.18- 1.02 ( m, IH), 0.6-0.5 (m, 2H), 0.31-0.25 (m, 2H).
Example 4.
Synthesis of 7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid methoxyl amide.
Figure imgf000053_0001
Using the same reaction conditions as in Example 3, 7-(4-bromo 2-fluoro- phenylamino)-5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid (0.2 g, 0.544 mmol) is reacted with methoxylamine hydrochloride (136 mg, 1.63 mmol) to yield the crude product. Purification of the product by column chromatography on silica gel (4% methanol in CHCI3) and then preparative HPLC gives the title compound in 16% yield. LC-MS purity: 99.27%, m/z= 396, 398.9, (M+ Br pattern).
H1NMR: (DMSO- D6300 MHZ): 11.4 (s, IH), 8.4 (s, IH), 7.7-7.6 (m, IH), 7.5-7.3 (m, 2H), 7.223 (t, IH), 5.3 (s, IH), 3.9 (t, 2H), 3.3-3.1 (m, 4H), 3.0 (s, 3H), 2.1 (t, 2H).
Example 5. Synthesis of 7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid amide.
Figure imgf000054_0001
Using the same reaction conditions as in Example 3, 7-(4-bromo 2-fluoro- phenylamino) -5-oxo-l,2,3, 5-tetrahydro indolizine 8-carboxylic acid (0.2 g, 0.544 mmol) is converted to the title compound with ammonium chloride and triethyl amine. The test compound is obtained as a white solid in 30% yield, following purification by column chromatography on silica gel (5% methanol in CHCI3). LC-MS purity: 98.74%, m/z= 366, 368, (M+ Br pattern)
H1NMR: (DMSO- D6 300 MHZ): 9.0 (s, IH), 7.7-7.6 (m, 2H), 7.4 (t, 2H), 5.3 (s, IH), 3.9 (t, 2H), 3.2-3.1 (m, 2H), 3.0 (s, 3H), 2.1 (t, 2H)
Example 6.
Synthesis of 7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8-carboxylic acid ethoxy amide.
Figure imgf000054_0002
Using the same reaction conditions as in Example 3, 7-(4-bromo 2-fluoro- phenylamino) -5-oxo-l,2,3, 5-tetrahydro indolizine 8-carboxylic acid (0.2 g, 0.54 mmol) is converted with ethoxylamine hydrochloride to the title compound. Purification of the product by column chromatography on silica gel (5% methanol in CHCI3), followed by preparative HPLC affords the test compound as a white solid in 28% yield. LC-MS purity: 99.27%, m/z= 410, 412, (M+ Br pattern).
H1NMR: (DMSO- D6300 MHZ): 11.4 (s, IH), 8.3 (s, IH), 7.7-7.5 (m, IH), 7.5-7.3 (m, 2H), 5.3 (s, IH), 4.0-3.8 (m, 4H), 3.4-3.2 (m, 2H), 2.1 (t, 2H), 1.2 (t, 3H).
Example 7.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carbaldehyde
Figure imgf000055_0001
To a solution of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxymethylamide (0.1 g, 0.25 mmol) in 5 ml dry THF under nitrogen is added dropwise 0.76 ml (0.76 mmol) of DIBAH-H (1.0 M solution in diethyl ether) over a period of 5 minutes at -78 C0. The reaction mixture is stirred at - 78 C0 for 4 hr and. quenched with a saturated aqueous ammonium chloride solution (10 ml). The reaction mixture is extracted with ethyl acetate and the combined organic extracts are washed with water and brine, then dried (anhydrous sodium sulfate) and concentrated. The title compound is obtained in 41% yield, following purification by column chromatography on silica gel (2% methanol in CH2Cl2). LC-MS purity: 90 %, m/z= 350, (M+2 Br pattern) HPLC: 92 %
H1 NMR: (DMSO- D6,, 300 MHZ): δ 10.0 (s, 1 H), 9.56 (s, IH), 7.54 (d, IH), 7.50 (s, 2H), 5.35 (s, IH), 4.0 (t, 2H), 3.55 (t, 2 H), 2.4-2.2 (m, 2H).
Example 8.
Step 1.
Synthesis of 7-Chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester
Figure imgf000055_0002
To a suspension of 7-hydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (500 mg, 2.2 mmol) in POCl3 (2g, 13.4mmol) is added TEA (0.226 g, 2.2 mmol) and the reaction mixture is stirred for 14 hours. The reaction mass is poured into ice water and the pH of the mixture is adjusted to 7 with an aqueous K2CO3 solution. The reaction mixture is extracted with EtOAc and the combined organic extracts are dried (anhydrous Na2SO4) and concentrated. The title compound is obtained in 74% yield, following purification by column chromatography on silica gel (1 :1 EtOAc-hexane, v/v). LC-MS purity: 100%, m/z= 242, (M+)
1H NMR (CDCl3, 300 MHZ): 6.60 (s,lH), 4.40 (q, 2H), 4.12 (t, 2H), 3.50 (t, 2H), 2.32-
2.19 (m, 2H), 1.40 ( t, 3H).
Step 2.
Synthesis of T-Chloro-ό-fluoro-S-oxo-l^^S-tetrahydro-indolizine-S-carboxylic acid ethyl ester
Figure imgf000056_0001
A mixture of 7-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (14.5 g, 0.06 mol) and l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane- bis(tetrafluoroborate) (44.7 g, 0.13 mol) in 700ml of CH3CN is heated at 80° C with stirring for 5-10 minutes; the heat source is then removed. The volatile components are removed under reduced pressure and the residual material is dissolved in water and extracted with EtOAc. The combined organic extracts are dried (anhydrous Na2SO4) and concentrated to give 14 g of the crude product. The title compound is obtained in 33% yield after column chromatography on silica gel (40% EtOAc in hexane) and is used in the next step without further purification. LC-MS purity: 87%, m/z =260, (M+).
Step 3.
Synthesis of T-Chloro-ό-fluoro-S-oxo-l^^S-tetrahydro-indolizine-S-carboxylic acid
Figure imgf000056_0002
To a solution of 120 ml of THF:MeOH (4:1, v/v) containing 5.2 g of 7-chloro-6-fluoro-
5-oxo-l,2,3, 5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (0.02 mol) is added 30ml of IN aqueous LiOH solution and the whole is stirred at ambient temperature for 3 hours. The pH of the reaction mixture is adjusted to 1 and it is extracted with EtOAc. The combined organic extracts are dried (anhydrous Na2SO4) and concentrated to yield the crude product. Trituration with EtOAc gives the title compound in 78% yield as a gray solid.
LC-MS purity: 95%, m/z= 232, (M+)
1H NMR (DMSO-D6, 300 MHZ): 13.4 (s, lH),s 4.08 (t, 2H), 3.30 (t, 2H), 2.18-2.06 (m,
2H).
Step 4.
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid.
Figure imgf000057_0001
A stirred solution of 2-fluoro-4-iodo-phenylamine (6.4 g, 0.027 mol) in 60 ml THF is treated with LDA (4 g, 0.037 mol) at -780C under nitrogen. After 20 minutes, a solution of THF (330 ml) containing 7-chloro-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (2.5 g, 0.011 mol) is added. The reaction mixture is stirred for 30 minutes more at -780C and then allowed to warm to ambient temperature. The reaction mixture is stirred for 3 days and the volatile components are removed under reduced pressure. The residual material is partitioned between 50ml of 3N HCl solution and 50ml of diethyl ether. After stirring for 15 minutes, the resulting solids are collected to give a 72% yield of the title compound as a light brown solid LC-MS purity: 96%, m/z =433, (M+)
1H NMR (DMSO-D6, 300MHZ): δ 13.8-13.6 (br s, IH), 9.42 (s, IH), 7.62 (d, IH), 7.48 (d, IH), 6.9-6.8 (m, IH), 4.04 (t, 2H), 3.46 (t, 2H), 2.18-2.04 (m, 2H).
Example 9.
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide
Figure imgf000058_0001
Using the same reaction conditions as in Example 3, a mixture of 6-fluoro-7-(2-fluoro- 4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (100 mg, 0.23 mmol), EDCI (133 mg, 0.69 mmol), and HOBt (93 mg, 0.69 mmol ) in 6 ml of dry DMF is stirred for 30 minutes and combined with O-cyclopropylmethyl-hydroxylamine (86 mg, 0.69 mmol) and TEA (70 mg, 0.69 mmol) to yield the title compound as a gray solid in 34% yield after column chromatography on silica gel (0-2% MeOH in CHCI3). LC-MS purity: 91%, m/z 500, (M-)
1H NMR (DMSO-D6, 300 MHZ): δ 11.40 (s, IH), 8.08 (s, IH), 7.58 (d, IH), 7.42 (d, IH), 6.86-6.76 (m, IH), 4.00 (t, 2H), 3.52 (d, 2H), 3.18 (t, 2H), 2.2-2.0 (m, 2H), 1.08- 0.98 ( m, IH), 0.57-0.47 (m, 2H), 0.27-0.19 (m, 2H).
Example 10.
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide
Figure imgf000058_0002
Using the same reaction conditions and reagents as described in Example 5, 6-fluoro-7- (2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (300 mg, 0.69 mmol) is converted to 200 mg of the crude title compound. Trituration with EtOAc and diethyl ether gives the test compound in 40% yield as a pale yellow solid.
LC-MS purity: 96%, m/z 432, (M+)
1H NMR (DMSO-D6, 300 MHZ): δ 8.58 (s, IH), 7.75 (d, 2H), 7.60 (d, IH), 7.45 (d, IH) 6.82-6.7 (m, IH), 4.02 (t, 2H), 3.3 (t, 2H), 2.2-2.08 (m, 2H).
Example 11. Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid
Figure imgf000059_0001
Using the identical reaction conditions and reagents as those in Example 8, Step 4, 4- bromo-2-fluoro-phenylamine (925 mg, 4.8 mmol) is combined with 7-chloro-6-fluoro- 5-oxo-l,2, 3,5-tetrahydro-indolizine-8-carboxylic acid (450 mg, 1.94 mol) to give the title compound in 60% yield as a light brown solid. LC-MS purity: 94%, m/z= 385, 387 (M+, Br Pattern)
1H NMR (DMSO-D6, 300 MHZ): δ 13.9-13.80 (br s, IH), 9.44 (s, IH), 7.56 (d, IH), 7.34 (d, IH), 7.18-6.9 (m, IH), 4.04 (t, 2H), 3.48 (t, 2H), 2.18-2.05 (m, 2H).
Example 12.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide
Figure imgf000059_0002
Using identical reaction conditions and reagents as to those in Example 9, 7-(4-bromo- 2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-ndolizine-8-carboxylic acid (100 mg, 0.25 mmol) is converted to the title compound as a white solid in 32% yield following silica gel chromatography (0-2% MeOH in CHCI3). LC-MS purity: 98%, m/z= 454, 456 (M+, Br pattern).
1H NMR (DMSO-D6, 300 MHZ): δ 11.40 (s, IH), 8.06 (s, IH), 7.54 (d,lH), 7.28 (d, IH), 7.04-6.94 (m, IH), 4.00 (t, 2H), 3.52 (d, 2H), 3.20 (t, 2H), 2.18-2.04 (m, 2H), 1.08-0.98 ( m, IH), 0.55-0.45 (m, 2H), 0.28-0.19 (m, 2H).
Example 13.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide
Figure imgf000060_0001
Using the same reaction conditions and reagents as described in Example 5, 7-(4- bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (250 mg, 0.64 mmol) ) is converted to 140 mg of the crude title compound. Trituration with EtOAc and diethyl ether gives the test compound in 25% yield as a light yellow solid.
LC-MS purity: 99%, m/z 384, 386 (M+, Br Pattern).
1H NMR (DMSO-D6, 300 MHZ): δ 8.58 (s, IH), 7.74 (d, 2H), 7.54 (d, IH), 7.29 (d, IH) 7.0-6.9 (m, IH), 4.00 (t, 2H), 3.3 (t, 2H), 2.19-2.08 (m, 2H).
Example 14.
Step 1.
Synthesis of 7-Hydroxy-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester :
Figure imgf000060_0002
A solution of 7-hydroxy-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (7.5 g, 33.6 mmol) in THF is added dropwise at 0° C to a stirred suspension of sodium hydride in THF under an inert atmosphere. The reaction mixture is allowed to warm to ambient temperature and is then treated with iodomethane. The resulting reaction mixture is stirred for 2 days (TLC monitoring, 100% EtOAc) and then is quenched with ice. The volatiles are removed under reduced pressure and the remaining aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed with brine and concentrated. Column chromatography of the crude product on silica gel (70% ethyl acetate in hexane) yields 38% of the title compound. 1H NMR (DMSO-D6): δ 11.5 (s, IH), 4.3 (q, 2H), 4.0 (t, 2H), 3.48 (t, 2H), 2.1 (q, 2H), 1.8, (s, 3H), 1.3 (t, 3H).
Step-2 Synthesis of 6-Methyl-5-oxo-7-trifluoromethanesulfonyloxy-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester
Figure imgf000061_0001
Using reaction conditions identical to those in Example 1, Step 3, 7-hydroxy-6-methyl- 5-oxo-l,2,3, 5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (0.75 g, 3.16 mmol) is converted to the title compound with triflic anhydride (1.06 g, 3.79 mmol) after stirring for 12 hours at ambient temperature. The test compound is obtained in 40% yield after silica gel column chromatography (25% ethyl acetate in hexane). 1H NMR (DMSO-D6): 4.40 (q, 2H), 4.20 (t, 2H), 3.5 (t, 2H), 2.3-2.2 (m, 2H), 2.05 (s,3H), 1.35 ( t, 3H).
Step 3.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester.
Figure imgf000061_0002
A stirred solution of toluene (100 ml) containing 6-methyl 5-oxo-7- trifluoromethanesulfonyloxy-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (0.47 g, 1.26 mmol), 2-fluoro-4-bromo-aniline (0.287 g, 1.26 mmol), cesium carbonate(0.617 g, 1.89 mmol), BINAP (0.6 g, 0.19 mmol), and Pd(OAc)2 ( 0.028 g, 0.126 mmol) is heated for 4 hours at 90 'C. . The reaction mixture is filtered and the filtrate is concentrated. The residual material is taken up in ethyl acetate and washed twice with brine, then dried (anhydrous Na2SO4) and concentrated. Column chromatography of the crude product on silica gel (75% ethyl acetate in hexane) affords the title compound in 19 % yield. LC-MS purity: 96.24%, m/z 409, (M+, Br pattern).
1H NMR (DMSO-D6): δ 8.5 (s, IH), 7.50 (d, IH), 7.25 (d, IH), 6.6 (t,lH), 4.2-4.0 (m, 4H), 3.45 (d, 2H), 2.2-2.1 (m, 2H), 1.70 ( t, 3H), 1.3 (t, 3H).
Example 15. Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid .
Figure imgf000062_0001
An aqueous NaOH solution (1 ml,l N) is added to 7-(4-bromo-2-fluoro-phenylamino)- 6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (40 mg, 0.10 mmol) in a solvent mixture of THF:MeOH (3:1, v/v). The resulting reaction mixture is stirred for 3 hours at room temperature. The pH of the reaction mixture is adjusted to 1.5 with IN aqueous HCl solution and the resulting precipitate is filtered, washed with water (20ml) and ethyl acetate (10ml) to afford the title compound in 53% yield. LC-MS purity: 99.2 %, m/z 381 (M+, Br pattern).
1H NMR (DMSO-D6): δ 13.30 (s, IH), 9.10 (s, IH) 7.5 (d, IH) 7.20 (d, IH), 6.5 (s, IH), 4.05 (t, 2H), 3.5 (t, 2H), 2.10 (t, 2H), 1.6 (s, 3H).
Example 16.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000062_0002
Using identical reaction conditions and reagents as in Example 9, 7-(4-bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (300 mg,
0.787 mmol) is converted to the title compound with 0-cyclopropylmethyl hydroxylamine in 8% yield, following purification by silica gel chromatography (1%
MeOH in CHCl3).
LC-MS purity: 92.7%, m/z 450 (M+, Br Pattern).
1H NMR (DMSO-D6): δ 11.20 (s, IH), 7.7 (s, IH), 7.5 (d, IH), 7.2 (d, IH), 6.56 (t,
IH), 4.0 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.18 (q, 2H), 1.78 ( s, 3H), 1.0 (s,lH), 0.5 (d,
2H), 0.2 (d, 2H).
Example 17.
Step l Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy)-amide.
Figure imgf000063_0001
To a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (300 mg, 0.787 mmol) in 6ml of dry DMF and 2 ml of dichloromethane is added EDCI (165 mg, 0.865 mmol) and HOBt (116 mg, 0.865 mmol) at 0° C. The resulting reaction mixture is stirred for 2 hrs at 0°.C and is then treated in succession with 0-(2-vinyloxy-ethyl)-hydroxylamine (71 mg, 0.787 mmol) and TEA (158 mg, 1.57 mmol). After 12 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated aqueous NaHCOs solution. The organic phase is dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residual material is chromatographed on silica gel (1% MeOH in CHCI3) to give 180mg of the title compound in low purity. LC MS: 31.7%, m/z= 466, (M+ Br pattern)
Step 2
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
Figure imgf000063_0002
Crude 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine -8-carboxylic acid (2-vinyloxy-ethoxy)-amide (180 mg, 0.386 mmol) is dissolved in ethanol containing ImI of IN HCl and stirred for 16 hours at room temperature. The reaction mixture is concentrated and the residue is dissolved in ethyl acetate. The organic phase is washed with brine, concentrated, and the residue is column chromatographed on silica gel (2 % MeOH in CHCI3) to afford the title compound in 30% yield.
LC MS: 96.5%, m/z= 440, (M+ Br pattern) HPLC: 94.05% 1H NMR (DMSO-D6): δ 11.20 (s, IH), 7.65 (s, IH), 7.48 (d, IH), 7.18 (d, IH), 6.5 (t, IH), 4.0 (t, 2H), 3.7 (t, 2H), 3.5 (s, 3H), 3.2 (t, 2H), 2.14 (quin, 2H), 1.72 ( s, 3H).
Example 18.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro
-indolizine-8-carboxylic acid amide.
Figure imgf000064_0001
To a solution of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ( 200 mg, 0.524 mmol) in 6 ml THF is added a THF solution containing TBTU (292 mg 0.787 mmol) and TEA (79 mg, 0.787 mmol) at 00C. The reaction mixture is allowed to slowly warm to room temperature and is then stirred for one hour. Ammonium chloride is added and the reaction mixture is stirred at ambient temperature for 12 hours more. The reaction mixture is concentrated and the residue is dissolved in ethyl acetate. The organic phase is washed with aqueous NaHCO3 solution and concentrated. The title compound is obtained in 25% yield after column chromatography on neutral alumina (2% MeOH in CHCI3). LC MS: 93.7%, m/z= 380, (M+ Br pattern). HPLC:98.7%
1H NMR (DMSO-D6): δ 7.7 (s,lH), 7.5 (dd, IH), 7.2 (d, IH), 6.5 (t, IH), 4.0 (t, 2H), 3.3 (s, 2H), 2.1 (quin, 2H), 1.78 ( s, 3H).
Example 19.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l, 2,3,5- tetrahydro-indolizine-8-carboxylic acid methoxy-amide.
Figure imgf000064_0002
Using the same reaction conditions and reagents as in Example 4, 7-(4-bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.525 mmol) is transformed to the title compound with methoxylamine hydrochloride (45 mg, 0.55 mmol). The test compound is obtained in 19% yield via column chromatography on silica (1% MeOH in CHCI3).
LC-MS purity: 96.42%, m/z= 410, (M+ Br pattern).
HPLC: 97.8%
1H NMR (DMSO-D6): δ 11.20 (s, IH), 7.7 (s, IH), 7.5-7.4 (dd, IH), 7.2 (d, IH), 6.5 (t,
IH), 4.0 (t, 2H), 3.5 (s, 3H), 3.2 (t, 2H), 2.1 (quin, 2H), 1.78 (s, 3H).
Example 20.
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethoxy-amide.
Figure imgf000065_0001
Using the same reaction conditions as in Example 3, 7-(4-bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (200 mg, 0.523 mmol) is reacted with ethoxylamine hydrochloride (53 mg, 0.55 mmol) to yield the title compound. The test sample is obtained in 23% yield following column chromatography on silica gel (1% MeOH in CHCI3). LC-MS purity: 95.58%, m/z=424, (M+ Br pattern) HPLC: 98.61%
1H NMR (DMSO-D6): δ 11.20 (s, IH), 7.7 (s, IH), 7.5-7.4 (dd, IH), 7.2 (d, IH) 6.5 (t, IH), 4.0 (t, 2H), 3.7 (q, 2H), 3.2 (t, 2H), 2.1 (quin, 2H), 1.78 (s, 3H), l.l(t, 3H).
Example 21.
Synthesis of 2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo~6, 7, 8, 9-tetrahydro-4H- quinolizine-1-carboxylic acid-cyclopropyl-methoxyamide.
Figure imgf000065_0002
Following the procedure set forth in Example 3, 150 mg of 2-(4-bromo-2-fluoro- phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l-carboxylic acid (0.39 mmol) is transformed to the title compound with O-cyclopropylmethylhydroxylamine. The title compound is obtained in 29% yield after column chromatography on silica gel (3% methanol in CHCl3).
LC-MS purity: 99.3%, m/z = 451, (M+ Br pattern)
1H NMR (DMSO-D6): δ 11.8 (s, IH), 7.64 (d, IH), 7.54 (s, IH), 7.4 (d, IH), 7.3 (t,
IH), 5.2 (s, IH), 3.8 (t, 2H), 3.7 (d, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H), 1.1-1.0 (m,
IH), 0.55-0.45 (m, 2H), 0.3-0.2 (m, 2H).
Example 22.
Step l
Synthesis of 2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H- quinolizine-1-carboxylic acid-(2-vinyloxy-ethoxy)-amide.
Figure imgf000066_0001
Using reaction conditions identical to those in Example 17, Step 1, 2-(4-bromo-2- fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine- 1 -carboxylic acid (200 mg, 0.52 mmol) in 5ml DMF is converted to the title compound with O-(2-vinyloxy- ethyl)-hydroxylamine (64 mg, 0.62 mmol). The purified product is obtained by column chromatography on silica gel (methanol: chloroform) in 62% yield.
Step 2
Synthesis of 2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H- quinolizine-1-carboxylic acid-(2-hydroxy-ethoxy)-amide.
Figure imgf000066_0002
Using reaction conditions identical to those in Example 17, Step 2, 2-(4-bromo-2- fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine- 1 -carboxylic acid-(2- vinyloxy-ethoxy)-amide (150 mg, 0.032 mmol) is transformed to the title compound which is obtained in 12% yield following preparative HPLC
LC-MS purity: 98.7%, m/z = 441, (M+ Br pattern).
1H NMR (DMSO-D6): δ 11.6 (s, IH), 7.68-7.58 (dd, 2H), 7.46-7.42 (dd, IH), 7.3 (t, IH), 5.2 (s, IH), 4.85 (t, IH), 4.0 (t, 2H), 3.8 (t, 2H), 3.6 (q, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H).
Example 23.
Synthesis of 2-(4-bromo-2-fluoro-phenylamino)-4-oxo--6,7,8,9-tetrahydro-4H- quinolizine-1-carboxylic acid methoxy-amide.
Figure imgf000067_0001
Using the same reaction conditions and reagents as in Example 5, 2-(4-bromo-2-fluoro- phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l-carboxylic acid (200 mg,
0.52 mmol) is transformed to the title compound with methoxylamine hydrochloride
(131 mg, 1.52 mmol). Purification of the product by column chromatography on silica gel (3.5% MeOH in CHCl3), followed by preparative HPLC, yields 25 mg of the test compound.
LC-MS purity: 96.4%, m/z = 409.9, (M+ Br pattern).
1H NMR (DMSO-D6): δ 11.65 (s, IH), 7.64 (d, IH), 7.59 (s, IH), 7.4 (d, IH), 7.3 (t,
IH), 5.2 (s, IH), 3.8 (t, 2H), 3.7 (s, 3H), 2.7 (t, 2H), 1.85-1.65 (m, 4H).
Example 24.
Synthesis of 2-(4-bromo-2-fluoro-phenylamino)-4-oxo~6,7,8,9-tetrahydro-4H- quinolizine-1-carboxylic acid ethoxy-amide.
Figure imgf000067_0002
Using the same reaction conditions and reagents as in Example 3, 2-(4-bromo-2-fluoro- phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l-carboxylic acid (200 mg, 0.52 mmol) is reacted with ethoxylamine hydrochloride (153 mg, 1.5 mmol) to afford 55mg (25% yield) of the title compound after preparative HPLC. LC-MS purity: 97.9%, m/z = 425.8, (M+ Br pattern).
1H NMR (DMSO-D6): δ 11.6 (s, IH), 7.64 (d, IH), 7.52 (s, IH), 7.4 (d, IH), 7.3 (t, IH), 5.2 (s, IH), 4.0 (q, 2H), 3.8 (t, 2H), 2.7 (t, 2H), 1.85-1.65 (m, 4H), 1.3-1.15 (m, 3H).
Example: 25
Steps 1 to 4 were performed in a manner similar to what has been described for example 1 and step 5 was performed in a manner similar to what has been described for example 2
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (3-hydroxy-propyl)-amide.
Figure imgf000068_0001
EDCI (390mg, 0.002mol) and HOBt (162mg, 0.002mol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro indolizine-8- carboxylic acid (250mg, O.OOlmol) in DMF (6mL) at O'C . The reaction mixture was stirred for 1 hr at O'C. To this were added 3-amino-propanol (0.156ml, 0.002mol), followed by TEA (ImL, 0.012mol). The reaction mixture was stirred overnight at RT. The reaction mixture was partitioned between ethyl acetate and cold water (2OmL). The organic layer was washed with NaHCO3 solution and concentrated. Purification by preparative HPLC affords 41mg (14.13% yield) of 7-(4-bromo-2-fluoro-phenylamino)- 5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-propyl)-amide. LC-MS purity: 97.2%, m/z = 426, 428 (M+ Br pattern) H1 NMR (DMSO-D6, 300 MHZ) δ 8.68 (s, IH), 8.28 (t, IH), 7.7-7.6 (m, IH), 7.5-7.3 (m, 2H), 5.49 (s, IH), 3.9 (t, 2H), 3.5 (t, 2H), 3.4-3.1 (m, 4H), 2.1 (quin, 2H), 1.7-1.5
(q, 2H)
Example: 26
Steps 1 to 4 were performed in a manner similar to what has been described for example 8
Step: 5
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-vinyloxy-ethoxy)-amide.
Figure imgf000069_0001
EDCI (530mg, 0.003mol) and HOBt (364mg, 0.003mol) were added to a stirred solution of 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.46mmol) in DMF (2OmL) and DCM (1OmL) at O'C. The reaction mixture was stirred for 2 hrs at O'C. O-(2-vinyloxy-ethyl)- hydroxylamine (280mg, 0.003mol), followed by TEA (272mg, 0.003mol) were added into the reaction flask and stirring was continued for 20 hrs at RT. The reaction mixture was partitioned between water and ethyl acetate (2OmL), The organic layer was washed with saturated NaHCO3 (2OmL), NH4Cl (2OmL), and brine solution (2OmL), dried over Na2SO4 and concentrated. The residual crude product (450mg) was used for the next step without a further purification. LCMS purity: 25%, m/z=518, (M+)
Step: 6
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
Figure imgf000069_0002
IN HCl (3mL) was added to a stirred solution of 6-fluoro-7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2-vinyloxy- ethoxy)-amide (450mg 0.22 mmol) in a 1:1 mixture of THF and EtOH (12mL). The reaction mixture was stirred for 90 minutes. The solvents from the reaction mixture were distilled and the reaction mixture was dissolved in water (3mL), pH was adjusted to 6 with 2N NaOH solution and partitioned with EtOAc. The organic layer was dried over Na2SO4 and concentrated. Purification by preparative HPLC affords 61mg (26% yield) of 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide as a white solid. LCMS purity: 95%, m/z= 491.9, (M+) HPLC: 96.6%
H1 NMR (DMSO-D6, 300 MHz) 11.5-11.4 (br s, IH), 8.2-8.0 (br s, IH), 7.6 (d, IH), 7.4 (d, IH), 6.82-6.72 (m, IH), 4.0 (t, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 3.2 (t, 2H), 2.2-2.0 (m, 2H)
Scheme: 7
Figure imgf000070_0001
Example: 27
Step: 1
Synthesis of 7-Chloro-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester.
Figure imgf000070_0002
TEA (58.27mmol, 8.4mL) was added to a stirred solution 7-hydroxy-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester (13g, 58.27mmol) in distilled POCI3 (32ml, 349mmol). The reaction mixture was stirred for 16hrs at RT under nitrogen atmosphere. POCI3 was distilled from the reaction mixture and the residue was poured into an ice cold water, basifϊed with saturated K2CO3 solution (pH= 8.5). The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, concentrated and the concentrate was purified by column chromatography (using silica gel, and 75% ethyl acetate in hexane as eluant) to afford 7.5mg (53.5% yield) of 7-chloro-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester as a yellow solid.
1H NMR (DMSO_D6, 300 MHz): δ 6.6-6.5 (br s, IH), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 3.5-3.3 (t, 2H), 2.3-2.2 (m, 2H), 1.4-1.3 (t, 2H)
Step: 2
Synthesis of T-Chloro-S-oxo-l^^S-tetrahydro-indolizine-δ-carboxylic acid.
Figure imgf000071_0001
IN LiOH (4OmL) was added to a stirred solution of 7-hydroxy-5-oxo-l,2,3,5- tetrahydro-indoline-8-carboxylic acid ethyl ester (7.5 g, 31.1mmol) in (4:1) THF:MeOH (75mL). The reaction mixture was stirred for 15hrs at room temperature. The reaction mixture was concentrated and acidified with IN HCl, the precipitate formed was collected, to afford 5.2g (78.7% yield) of 7-chloro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid as a white solid. LC-MS purity: 99%, m/z= 212, (M-I)
H1 NMR (DMSO- D6, 300 MHz): δ 13.25-13.15 (br s, IH), 6.4 (s, IH), 4.0 (t, 3H), 2.15-2.05 (m, 3H).
Step: 3
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid.
Figure imgf000072_0001
Lithiumdiisopropylamide (16.5ml, 32.8 mmol) was added to a stirred solution of 2- fluoro-4-iodoaniline (5.6g, 23.47mmol) in dry THF (4OmL) at -780C under nitrogen atmosphere. This was followed by addition of 7-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2g, 9.38mmol) in dry THF(150mL) and the resulting mixture was stirred first for 30min at -780C and then at RT for the next 5 days. The reaction mixture was concentrated and acidified with IN HCl till the pH was about 2. The precipitate formed was collected and washed with diethyl ether to afford 2.5g (65.7% yield) of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid as a white solid. LC-MS purity: 92.8%, m/z= 414.8, (M+l)
H1 NMR (DMSO-D6, 300 MHz) δ 13.45-13.35 (br s, IH), 10.05-9.95 (br s, IH), 7.8 (dd, IH), 7.6 (d, IH), 7.4-7.2 (t, IH), 5.4-5.3 (s, IH), 4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.1-2.0 (m, 2H)
Example: 28
Steps 1 to 3 were performed in a manner similar to what has been described for example 27
Step: 4
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid amide.
Figure imgf000072_0002
EDCI (0.415mg, 2.17mmol) and HOBt (0.293mg, 1.7mmol) were added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid (0.300mg, 0.72mmol) in DMF (5mL) and TEA (0.05mL) at O'C. The reaction mixture was stirred for 30minutes at O'C under nitrogen atmosphere. This was followed by addition NH4Cl (0.115mg, 2.17mmol), followed by TEA (0.3ml, 2.17mmol) and the reaction mixture was stirred for 6hrs at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine solution. The precipitate formed was collected to afford 0.040mg (13% yield) of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indo lizine-8- carboxylic acid amide as a white solid.
LC-MS purity: 98.7%, m/z= 412, (M-I)
H1 NMR (DMSO-D6, 300 MHz) δ 9.0 (br s, 2H), 7.7 (dd, IH), 7.7-7.6 (d, IH), 7.3-7.2
(t, IH), 5.5 (s, IH), 3.9 (t, 2H), 2.1-2.0 (m, 2H)
Example: 29
Steps 1 to 3 were performed in a manner similar to what has been described for example 27
Step: 4
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000073_0001
EDCI (O.lOlmg, 0.53mmol) and HOBt (0.072mg, 0. 53mmol) were added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indo lizine-8- carboxylic acid (0.200mg,0.48mmol) in DMF (4mL) and TEA (0.1 ml, 1.44mmol) at RT. The reaction mixture was stirred for 30minutes at RT under nitrogen atmosphere. This was followed by addition of O-cyclopropylmethyl-hydroxylamine hydrochloride (0.072mg, 0. 57mol), TEA (0.4 ml, 1.44mmol) and the reaction mixture was stirred for 18hrs at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, NaHCO3 and brine solution, dried over anhydrous Na2SO4 and concentrated. The residue was recrystallised with DCM (5mL) and methanol (ImL) to afford 0.059mg (25% yield) of 7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylicacid cyclopropylmethoxy-amide as a brown solid. LC-MS purity: 97%, m/z= 481.9, (M-I)
H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.3 (br s, IH), 8.3-8.2 (br s, IH) 7.7 (dd, IH) 7.6-7.5, (d, IH), 7.2 (t, IH), 5.4 (s, IH), 3.9 (t, 2H), 3.7-3.6 (d, 2H), 3.2-3.1 (m, 2H), 2.1-2.0 (m, 2H), 1.1-1.0 (m, IH), 0.5-0.4 (m, 2H), 0.3-0.2 (m, 2H) Example: 30
Steps 1 to 3 were performed in a manner similar to what has been described for example 27
Step: 4
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid ethyl ester.
Figure imgf000074_0001
Concentrated H2SO4 (0.6mL) was added to a stirred solution of 7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetra hydro-indolizine-8-carboxylicacid (0.300mg, 0.72mol) dissolved in EtOH (5mL) and the reaction mixture was stirred for 3 days at 850C under nitrogen atmosphere. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was washed with NaHCO3 , brine solution, concentrated and washed with diethyl ether. Purification by column chromatography (using silica gel, and 1.5% methanol in chloroform as the eluant) affords 0.095mg, (29.6% yield) of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester as a white solid. LC-MS purity: 96%, m/z= 443, (M+ 1)
H1 NMR (DMSO-D6, 300 MHz) δ 9.5-9.4 (br s, IH), 7.8 (dd, IH) 7.6 (d, IH) 7.3-7.2 (m, IH), 5.4-5.3 (br s, IH), 4.4-4.2 (m, 2H), 3.9 (t, 2H), 3.5 (t, 2H), 2.1-2.0 (m, 2H), 1.4-1.2 (m, 3H)
Example: 31
Steps 1 to 3 were performed in a manner similar to what has been described for example 27
Step: 4
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid (2-vinyloxy-ethoxy)-amide
Figure imgf000074_0002
EDCI (0.138mg, 0.72mmol) and HOBt (0.097mg, 0.72mmol) were added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid (0.200mg,0.48mmol) in DMF (5mL) and TEA (0.13 ml, 0.96mmol) at RT. This was followed by addition O-(2-vinyloxy-ethyl)-hydroxylamine (0.99mg, 0.96mmol), TEA (0.13 ml, 0.96mmol) and the reaction flask was stirred for 5hrs at RT under nitrogen atmosphere. The reaction mixture was diluted with water and partitioned with EtOAc. The organic layer was washed with NH4Cl, NaHCOs, brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by preparative HPLC affords 135mg (56% yield) of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-vinyloxy-ethoxy)-amide as a brown gummy solid.
Step: 5
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid (2-hydroxy-ethoxy)-amide.
Figure imgf000075_0001
IN HCl (1.5mL) and EtOH (3mL) were added to a stirred solution of 7-(2-fluoro-4- iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid-(2-vinyloxy- ethoxy)-amide (0.135mg, 0.27mmol) and the reaction mixture was stirred for 3 hrs at RT. The pH was adjusted to 5-7 with 2N NaOH solution. The reaction mixture was extracted with EtOAc. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by preparative HPLC affords 12mg (10% yield) of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide as a white solid. LC-MS purity: 98.9%, m/z= 473.9, (M+l)
H1 NMR (DMSO-D6, 300 MHz) 11.4-11.3 (br s, IH), 8.3-8.2 (br s, IH), 7.8-7.7 (dd, IH) 7.6-7.5 (d, IH) 7.2-7.1 (m, IH), 5.4-5.3 (br s, IH), 4.0-3.8 (m, 4H), 3.6 (t, 2H), 3.2 (t, 2H), 2.1-2.0 (m, 2H)
Example: 32 Steps 1 to 3 were performed in a manner similar to what has been described for example 27 Step: 4
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide.
Figure imgf000076_0001
EDCI (0.280mg, 0.00 lmol) and HOBt (0.197mg, O.OOlmmol) were added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylicacid (0.200mg, 0.0005mol) in DMF (5mL), TEA (0.005mL) and chloroform (2mL) at O0C. The reaction mixture was stirred for 1.30hrs at O0C under nitrogen atmosphere. This was followed by addition O-methoxy-hydroxylamine hydrochloride (0.121mg, O.OOlmol), followed by TEA (0.2ml, O.OOlmol) and the reaction mixture was stirred for 18hrs at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, NaHCOs and brine solution. The reaction mixture was dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by preparative HPLC to afford 6mg (2.8% yield) of 7-(2- fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide as a white solid. LC-MS purity: 98%, m/z= 443.8, (M+l)
H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.3 (br s, IH), 8.3-8.2 (br s, IH) 7.7 (dd, IH) 7.5, (d, IH), 7.2-7.1 (t, IH), 5.3 (s, IH), 3.9 (t, 2H), 3.8-3.6 (br s, 2H), 3.3-3.2 (m, 2H), 2.1-2.0 (m, 2H)
Example: 33
Steps 1 to 3 were performed in a manner similar to what has been described for example 27
Step: 4
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid ethoxy-amide.
Figure imgf000077_0001
EDCI (0.277mg, 0.00 lmol) and HOBt (0.200mg, O.OOlmmol) were added to a stirred solution of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylicacid (0.200mg, 0.0005mol) in DMF (5mL), TEA (O.lmL) and DCM (2mL) at O0C. The reaction mixture was stirred for 1.30hrs at O0C under nitrogen atmosphere. This was followed by addition O-ethoxy-hydroxylamine hydrochloride (0.141mg, 0.00 lmol), followed by TEA (0.2ml, 0.00 lmol) and the reaction mixture was stirred for 18hrs at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, NaHCOs and brine solution. The reaction mixture was dried over anhydrous Na2SO4 and concentrated. Purification by preparative HPLC affords 13mg (6% yield) of 7-(2-fluoro-4-iodo-phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide as a white solid. LC-MS purity: 98%, m/z= 457.8, (M+l)
H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.3 (br s, IH), 8.3-8.25 (br s, IH) 7.8-7.7 (d, IH) 7.6-7.5, (d, IH), 7.3-7.1 (t, IH), 5.4 (s, IH), 4.0-3.8 (m, 4H), 3.3-3.0 (m, 2H), 2.1- 2.0 (t, 2H), 1.3-l.l(t, 3H)
Example: 34
Steps 1 to 4 were performed in a manner similar to what has been described for example 1 and step 5 was performed in a manner similar to what has been described for example 2
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide.
Figure imgf000077_0002
EDCI (155mg , 0.816mmol) and HOBt (HOmg, 0.816mmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid (0.2 g, 0.544mmol) in DMF (6mL) at O'C. The reaction mixture was stirred for 1 hr at O'C. This was followed by addition O-(4,4-dimethyl-[l,3]dioxolan-2- ylmethyl)-hydroxylamine (180mg, 0.653mmol), TEA (0.45ml, 3.264mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was partitioned between ethyl acetate (5OmL) and cold water (5OmL). The organic layer was washed with saturated NaHCOs solution, dried over Na2SO4 and concentrated. Purification by column chromatography (using silica gel, 5% methanol in chloroform as eluant) afford 50mg (19.13% yield) of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide as the required product.
Step: 7
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide.
Figure imgf000078_0001
IN HCl (ImL) was added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-5- oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4- ylmethoxy)-amide (50mg, O.OlOmmol) dissolved in ethanol (2mL). The reaction mixture was stirred for 3 hrs at RT. Ethanol was distilled and the reaction mixture was partitioned between water and ethylacetate (2OmL). The organic layer was dried over Na2SO4, concentrated and the concentrate was purified by the recrystallization using DCM to afford 25mg (17.35% yield) of 7-(4-bromo-2-fluoro-phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide as the required product.
LC-MS: 95.8%; m/z= 456 (M+l), 458 (M+2) HPLC: 97.3%
H1NMR (DMSO-D6, 300 MHz): δ 11.2 (br s, IH), 8.3-8.2 (br s, IH), 7.6-7.5 (d, IH), 7.5-7.3 (m, 2H), 5.3 (s,lH), 4.9 (d, IH), 4.6-4.4 (t, IH), 4.0-3.8 (m, 3H), 3.8-3.5 (m, 2H), 3.4 (m, 2H), 3.3-3.2 (m, 2H), 2.1-2.0 (m, 2H)
Scheme 8:
Figure imgf000079_0001
Example: 35
Step: 1
Synthesis of T-Chloro-l^^^-tetrahydro-indolizine-δ-carboxylic acid ethyl ester.
Figure imgf000079_0002
TEA (58.27mmol, 8.4mL) were added to a stirred solution of 7-hydroxy-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester (13g, 58.27mmol) in distilled POCI3 (32ml, 349mmol) and the reaction mixture was stirred for 16hrs at room temperature under nitrogen atmosphere. POCI3 was distilled, the reaction mixture was poured into an ice cold water and basified with saturated K2CO3 solution to a pH of about 8.5. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel ,75% ethyl acetate in hexane as the eluant) to afford 7.5mg (53.5% yield) of 7-chloro-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester as a yellow solid.
1H NMR (DMSO-D6, 300 MHz): δ 6.6-6.5 (br s, IH), 4.4-4.3 (m, 2H), 4.2-4.1 (m, 2H), 3.5-3.3 (t, 2H), 2.3-2.2 (m, 2H), 1.4-1.3 (t, 2H) Step: 2
Synthesis of ό^-Dichloro-S-oxo-l^^S-tetrahydro-indolizine-S-carboxylic acid ethyl ester.
Figure imgf000080_0001
NCS (304mg, 0.002282mol) was added to a solution of 7-chloro-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester (500mg, 0.0020 lmol) dissolved in DMF and the reaction mixture was stirred for 18hrs at RT under nitrogen atmosphere. The reaction mixture was extracted with ethylacetate, washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford 400mg (70% yield) of βJ-dichloro-S-oxo-l^^^-tetrahydro-indolizine-S-carboxylic acid ethyl ester as the required product.
1H NMR (DMSO-D6, 300 MHz): δ 4.3-4.2 (m, 2H), 4.1-4.0 (t, 2H), 3.3 (t, 2H), 2.2-2.1 (m, 2H), 1.3 (t, 3H) LCMS: 78%; m/z=278, M+2 HPLC: 89%
Step: 3
Synthesis of ό^-Dichloro-S-oxo-l^^S-tetrahydro-indolizine-S-carboxylic acid.
Figure imgf000080_0002
IN LiOH (1OmL) was added to a stirred solution 6,7-dichloro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester (400mg, O.OOlmol) in (4:1) THF:MeOH (1OmL) and the reaction mixture was stirred for 3hrs at RT. The reaction mixture was concentrated and acidified with IN HCl to a pH of about 2. The precipitate was collected under reduced pressure to afford 375mg (100% yield) of 6,7-dichloro-5- oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid as the required product.
H1 NMR (DMSO-D6, 300 MHZ): δ 13.2 (s, IH), 4.1-4.0 (t, 2H), 3.3 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 92%; m/z= 248, M+l; 249.7, M+2
HPLC: 90.8% Step: 4
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid.
Figure imgf000081_0001
n-Butyl lithium (2ml, 0.003mol) were added dropwise to a stirred solution of diisopropyl amine (0.65ml, 0.005mol) in dry THF (4OmL) over a period of 5mins at - 78'C and the reaction mixture was stirred for 30 minutes followed by addition of A- bromo-2-fluoro-phenylamine (462mg, 0.002mol) dissolved in dry THF (5mL) at -78'C. The reaction mixture was stirred for a further 30 minutes, and was followed by addition of β^-dichloro-S-oxo-l^^^-tetrahydro-indolizine-S-carboxylic acid (200mg, O.OOlmol) dissolved in dry THF (1OmL) at -78'C with the stirring over a period of 30mins. The stirring was continued for a further 16 hrs at RT. THF was distilled and the residual mass was acidified by addition of IN HCl, followed by ether with stirring for lOmins. The precipitate formed was collected, washed with ether and dried to afford 232mg (72% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid as the required product.
H1 NMR (DMSO-D6, 300 MHz) δ 13.3 (s, IH), 9.6-9.5 (br s, IH), 7.6-7.5 (dd, IH), 7.3 (d, IH), 6.9 (t, IH), 4.1-4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.2-2.1 (m, 2H) LCMS: 96%; m/z= 400.9, M+l HPLC= 95.5%
Example: 36
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000081_0002
Procedure:
EDCI (143mg, O.OOlmol) and HOBt (102mg, 0.001 mo 1) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (lOOmg, 0.0002mol) in DMF (3mL) at O'C. The reaction mixture was stirred for 1.5 hrs at O'C. This was followed by addition of O- cyclopropylmethyl-hydroxylamine hydrochloride (92mg, O.OOlmol), TEA (0.1ml, O.OOlmol) at O0C. The reaction mixture was stirred for 18 hours at RT. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with saturated NH4Cl solution, NaHCOs solution, and brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by preparative HPLC affords 42mg (36% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide as the required product. H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.2 (br s, IH), 8.04-7.96 (br s, IH), 7.5 (d, IH), 7.3 (d, IH), 6.9 (t, IH), 4.1-4.0 (t, 2H), 3.2 (d, 2H), 3.1 (t, 2H), 2.2-2.1 (m, 2H), 1.0 -0.9(m, IH), 0.5 (d, 2H), 0.3 (s, 2H) LCMS: 100%; m/z= 471.7, M+l HPLC= 99%
Example: 37
Steps 1 to 4 were performed in a manner similar to what has been described for example 1
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxy-amide.
Figure imgf000082_0001
EDCI (286mg, O.OOlmol) and HOBt (202mg, O.OOlmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0005mol) in dry DMF (5mL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C. This was followed by addition of O- methoxy-hydroxylamine hydrochloride (125mg, O.OOlmol), TEA (0.21ml, O.OOlmol) at O'C. The reaction mixture was stirred for 16hrs at RT under nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCOs solution and brine solution, dried over anhydrous Na2SO4, concentrated and the crude product was washed with methanol to afford 0.02Og (9.3% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide as a white solid. H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.2 (br s, IH), 8.0 (br s, IH), 7.5 (dd, IH), 7.3 (d, IH), 6.9 (t, IH), 4.0 (t, 2H), 3.4 (s, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H) LCMS: 90%; m/z= 431.9, M+l HPLC: 99%
Example: 38
Steps 1 to 4 were performed in a manner similar to what has been described for example 1
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide.
Figure imgf000083_0001
EDCI (286mg, O.OOlmol) and HOBt (202mg, O.O.OOlmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.005mol) in dry DMF (5mL) at O0C. The reaction mixture was stirred for 1.30hrs at O0C. This was followed by addition of NH4Cl (80mg, O.OOlmol), followed by TEA (0.2ml, O.OOlmol) at O'C. The reaction mixture was stirred for 16hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCO3 solution and brine solution, dried over anhydrous. Na2 S O4 and concentrated to afford 0.02Og (9.3% yield) of 7-(4-bromo-2-fiuoro-phenylamino)-6-chloro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid amide as the required product. H1 NMR (DMSO-D6, 300 MHz) δ 8.44-8.4 (br s, IH), 7.64-7.58 (br s, 2H), 7.5 (dd, IH), 7.2 (d, IH), 6.9-6.8 (t, IH), 4.0 (t, 2H), 3.3-3.2 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 94.2%; m/z= 401.9, M+l HPLC: 94.5%
Example: 39
Steps 1 to 4 were performed in a manner similar to what has been described for example 1
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethoxy-amide.
Figure imgf000084_0001
EDCI (286mg, 0.00 lmol) and HOBt (202mg, 0.00 lmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0005mol) in dry DMF (5mL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C. This was followed by addition of O- ethoxy-hydroxylamine hydrochloride (145mg, O.OOlmol), followed by TEA (0.2ml, O.OOlmol) at O'C. The reaction mixture was stirred for 18hrs at RT under nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCO3 solution and brine solution, dried over anhydrous.Na2SO4, concentrated and the crude product was recrystallised using methanol to afford 52g (23.6% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6- chloro-S-oxo-l^^^-tetrahydro-indolizine-S-carboxylic acid ethoxy-amide as the required product.
H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.2 (br s, IH), 8.1-7.9 (br s, IH), 7.5 (dd, IH), 7.3 (d, IH), 6.9 (t, IH), 4.0 (t, 2H), 3.6-3.5 (m, 2H), 3.1 (t, 2H), 2.2-2.0 (m, 2H), 1.1 (t, 3H)
LCMS: 100%; m/z =445.7, M+l; 443.8, M-I HPLC: 96%
Example: 40
Steps 1 to 4 were performed in a manner similar to what has been described for example 1 Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide.
Figure imgf000085_0001
EDCI (572mg, 0.003mol) and HOBt (191.7mg, 0.003mol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (400mg, O.OOlβmol) in dry DMF (1OmL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C. This was followed by addition of O- (2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-hydroxylamine (440mg, 0.003mol), TEA (0.4ml, 0.003mol) at O'C and stirring was continued for 16hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCOs solution and brine solution, dried over anhydrous. Na2 S O4, concentrated. Purification by column chromatography (using silica gel, 2% methanol and chloroform as eluant) affords 0.3g (56.8% yield) of 7-(4-bromo-2-fluoro- phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2- dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide as the required product. H1 NMR (DMSO-D6, 300 MHz) δ 11.4 (br s, IH), 7.94-8.06 (br s, IH), 7.5 (dd, IH), 7.3-7.24 (d, IH), 6.9 (t, IH), 4.2-4.1 (m, IH), 4.1-4.0 (m, 3H), 3.6-3.5 (m, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H), 0.8-0.7 (s, 6H) LCMS: 65%; m/z =529.9 M+l
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide.
Figure imgf000085_0002
IN HCl (0.6mL) were added to a stirred solution of 7-(4-bromo-2-fluoro- phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2- dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide (300mg, O.OOlmol) dissolved in EtOH (12mL). The reaction mixture was stirred for 2 hrs at room temperature. Ethanol was distilled and the residual mass was extracted with EtOAc. The organic layer was washed with water, saturated NaHCOs solution, brine solution and dried over anhydrous Na2SO4 and concentrated. Recrystallization from methanol affords 50mg (18.5% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide as a white solid. H1 NMR (DMSO-D6, 300 MHz) δ 11.4 (br s, IH), 8.0 (br s, IH), 7.5-7.4 (dd, IH), 7.3- 7.2 (d, IH), 6.9 (t, IH), 4.8 (d, IH), 4.6-4.5 (t, IH), 4.0 (t, 2H), 3.7-3.5 (m, 2H), 3.5-3.4 (m, IH), 3.2-3.1 (t, 2H), 2.1-2.0 (m, 2H). LCMS: 85%; m/z= 491.7, M+l HPLC= 96%
Example: 41
Steps 1 to 3 were performed in a manner similar to what has been described for example 1
Step: 4
Synthesis of 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid.
Figure imgf000086_0001
n-Butyl lithium (20ml, 0.032mol) was added drop wise for 5mins to a stirred solution of diisopropyl amine (4.5ml, 0.032mol) in dry THF (5mL) at -78'C and the reaction mixture was stirred for 30 minutes. This was followed by the addition of 2-fluoro-4- iodo-phenylamine (5.75g, 0.002mol) dissolved in dry THF (1OmL) at -78'C. The reaction mixture was stirred for a further 30 minutes and this was followed by addition of ό^-dichloro-S-oxo-l^^^-tetrahydro-indolizine-S-carboxylic acid (2g, 0.008mol) dissolved in dry THF (13OmL) at -78'C with stirring over a period of 30mins. The stirring was continued for a further 2 days at RT under nitrogen atmosphere. THF was distilled and the residual reaction mixture was acidified by addition of IN HCl. Addition of diethyl ether, stirring for lOmins yields a precipitate which was collected, washed with diethyl ether and dried to afford 2.3g (63.8% yield) of 6-chloro-7-(2- fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid as the required product.
H1 NMR (DMSO-D6, 300 MHz) δ 13.6 (s, IH), 9.5 (br s, IH), 7.6 (dd, IH), 7.4 (d,
IH), 6.7 (t, IH), 4.1-4.0 (t, 2H), 3.5-3.4 (t, 2H), 2.2-2.1 (m, 2H)
LCMS: 92%; m/z= 448.7
HPLC: 98%
Example: 42
Step: 5
Synthesis of 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000087_0001
EDCI (256mg, 0.00 lmol) and HOBt (181mg, 0.00 lmol) were added to a stirred solution of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0004mol) in dry DMF (5mL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C. This was followed by addition of O- cyclopropylmethyl-hydroxylamine hydrochloride (165mg, O.OOlmol), TEA (0.2ml, O.OOlmol) at O'C. The reaction mixture was stirred for 16hrs at RT under nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NH4Cl, saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, concentrated and the concentrate was washed with methanol to afford 55mg (24% yield) of 6-chloro-7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide as the required product.
H1 NMR (DMSO-D6, 300 MHz) δ 11.25-11.2 (br s, IH), 8.0-7.94 (br s, IH), 7.6-7.5 (dd, IH), 7.4 (d, IH), 6.8-6.7 (t, IH), 4.0 (t, 2H), 3.2 (d, 2H), 3.1 (t, 2H), 2.1 (t, 2H), 1.0-0.9 (m, IH), 0.5 (d, 2H), 0.3 (s, 2H) LCMS: 94.5%; m/z= 517.6 HPLC: 94.79% Example: 43
Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
Step: 5
Synthesis of 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxy-amide.
Figure imgf000088_0001
EDCI (256mg, 0.00 lmol) and HOBt (181mg, 0.00 lmol) were added to a stirred solution of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0004mol) in dry DMF (1OmL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C. This was followed by addition of O- methyl-hydroxylamine hydrochloride (l l lmg, O.OOlmol), followed by TEA (0.2ml, O.OOlmol) at O'C. The reaction mixture was stirred for 16hrs at RT under nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCOs solution and brine solution, dried over anhydrous Na2SO4, concentrated and the concentrate was washed with methanol to afford 105mg (48% yield) of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5- oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid methoxy-amide as the required product.
H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.2 (br s, IH), 8.02-7.96 (br s, IH), 7.6-7.5 (dd, IH), 7.4 (d, IH), 6.8-6.7 (t, IH), 4.0 (t, 2H), 3.4 (s, 3H), 3.1 (t, 2H), 2.1-2.0 (m, 2H)
LCMS: 90%; m/z= 477.9 HPLC: 96.6%
Example: 44
Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
Step: 5 Synthesis of 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide.
Figure imgf000089_0001
EDCI (256mg, 0.00 lmol) and HOBt (181mg, 0.00 lmol) were added to a stirred solution of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0004mol) in dry DMF (5mL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C under nitrogen atmosphere. This was followed by addition of NH4Cl (0.07 Ig, 0.00 lmol), followed by TEA (0.2ml, O.OOlmol) at O'C. The reaction mixture was stirred for 16hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, concentrated and the concentrate was washed with methanol to afford 60mg (30% yield) of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide as the required product.
H1 NMR (DMSO-D6, 300 MHz) δ 8.46-8.4 (br s, IH), 7.68-7.52 (m, 3H), 7.4 (d, IH), 6.7 (t, IH), 4.0 (t, 2H), 3.3-3.2 (t, 2H), 2.1-2.0 (m, 2H) LCMS: 98.68%; m/z= 447.8 HPLC: 97.5%
Example: 45
Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
Step: 5
Synthesis of 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethoxy-amide.
Figure imgf000089_0002
EDCI (256mg, 0.001 mo 1) and HOBt (181mg, 0.001 mo 1) were added to a stirred solution of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.000446mol) in dry DMF (5mL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C under nitrogen atmosphere. This was followed by addition of O-ethyl-hydroxylamine hydrochloride (130mg, O.OOlmol), TEA (0.2ml, O.OOlmol) at O'C. The reaction mixture was stirred for 18hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCOs solution and brine solution, dried over anhydrous Na2SO4, concentrated and the concentrate was washed with methanol to afford 105mg (48% yield) of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethoxy-amide as the required product. H1 NMR (DMSO-D6, 300 MHz) δ 11.25-11.2 (br s, IH), 8.02-7.94 (br s, IH), 7.6-7.5 (d, IH), 7.4 (d, IH), 6.8-6.7 (t, IH), 4.0 (t, 2H), 3.6-3.5 (m, 2H), 3.1 (t, 2H), 2.1-2.0 (m, 2H), 1.1 (t, 3H) LCMS: 99%; m/z= 491.6 HPLC: 96%
Example: 46
Steps 1 to 3 were performed in a manner similar to what has been described for example 1 and step 4 was performed in a manner similar to what has been described for example 6.
Step: 5
Synthesis of 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide.
Figure imgf000090_0001
EDCI (256mg, O.OOlmol) and HOBt (180mg, O.OOlmol) were added to a stirred solution of 6-chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0004mol) in dry DMF (5mL) at O'C. The reaction mixture was stirred for 1.30hrs at O0C under nitrogen atmosphere. This was followed by addition of O-(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-hydroxylamine (196mg, O.OOlmol), TEA (0.2ml, O.OOlmol) at O'C. The reaction mixture was stirred for 18hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water, saturated NaHCOs solution and brine solution, dried over anhydrous Na2SO4 and concentrated to afford 170mg (66% yield) of 6- chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide as the required product. LCMS: 61%; m/z= 577.8, M+l
Step: 6
Synthesis of 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide.
Figure imgf000091_0001
IN HCl (0.6mL) was added to a stirred solution of 6-chloro-7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2,2-dimethyl- [l,3]dioxolan-4-ylmethoxy)-amide (170mg, 0.0003mol) dissolved in EtOH (6mL). The reaction mixture was stirred for 2 hrs at room temperature. Ethanol was distilled and the crude product was purified by recrystallization using methanol to afford 25mg (17.35% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide as a white solid.
H1 NMR (DMSO-D6, 300 MHz) δ 11.4-11.35 (br s, IH), 8.0-7.96 (br s, IH), 7.6-7.5 (dd, IH), 7.4 (dd, IH), 7.4 (d, IH), 6.8 (t, IH), 4.8 (d, IH), 4.6 (t, IH), 4.0 (t, 2H), 3.7- 3.4 (m, IH), 3.1 (t, 2H), 2.1-2.0 (m, 2H) LCMS: 85%; m/z= 491.7, M+l HPLC: 96%
Example: 47
Steps 1 to 3 were performed in a manner similar to what has been described for example 8 Step: 4
Synthesis of 6-Fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid.
Figure imgf000092_0001
LDA (416mg, 0.004mol) was added to a solution of 2-fluoro-4-trifluoromethyl- phenylamine (484mg, 0.003mol) in THF (1OmL) at -780C and the resulting mixture was stirred for lhr at -780C. This was followed by addition of 7-chloro-6-fluoro-5-oxo-
1,2,3, 5-tetrahydro-indolizine-8-carboxylic acid (250mg, O.OOlmol) in THF (3OmL) at -
780C and stirring was continued for a further 18hrs at RT. THF from the reaction mixture was distilled and this was followed by addition of IN HCl (5mL) and ether
(1OmL). The reaction mixture was stirred for 15 minutes and the precipitate was collected to afford 150mg (37% yield) of 6-fluoro-7-(2-fluoro-4-trifluoromethyl- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid as the required product.
LC-MS purity: 100%, m/z =375, (M+)
HPLC: 91.4%
1H NMR (DMSO-D6, 300 MHz): δ 13.8-13.6 (br s, IH), 9.6 (s, IH), 7.7 (d, IH), 7.52
(d, IH), 7.15 (q, IH), 4.1 (t, 2H), 3.5 (t, 2H), 2.2-2.1 (m, 2H).
Example: 48
Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 47
Step: 5
Synthesis of 6-Fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000092_0002
EDCI (138mg, O.OOlmol) and HOBt (98mg, O.OOlmol) were added to a stirred solution of 6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (90mg, 0.0002mol) in DMF (6mL) and the reaction mixture was stirred for 30mins at RT. This was followed by addition of O- cyclopropylmethyl-hydroxylamine hydrochloride (90mg, O.OOlmol) and TEA (73mg, O.OOlmol). The reaction mixture was stirred for 20 hrs at RT. The reaction mixture was partitioned between water and ethyl acetate (2OmL). The organic layer was washed with saturated NaHCO3 (2OmL), NH4Cl (2OmL), and brine solution (2OmL), dried over Na2SO4, concentrated and the concentrate was dissolved in methanol (0.5mL) and diethyl ether (1OmL). The precipitate formed was collected to afford 35mg (33% yield) of 6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy- amide as the required product. LCMS purity: 100%, m/z=443, (M+) HPLC: 94.3%
1H NMR (DMSO-D6, 300 MHz): δ 11.40 (s, IH), 8.4 (s, IH), 7.65 (d,lH), 7.43 (d, IH), 7.12-7.02 (m, IH), 4.1 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.2-2.1 (m, 2H), 1.05-0.95 (m, IH), 0.52-0.42 (m, 2H), 0.25-0.15 (m, 2H).
Example: 49
Steps 1 to 3 were performed in a manner similar to what has been described for example 8
Step: 3a
Synthesis of 2-Fluoro-4-thiocyanato-phenylamine.
Figure imgf000093_0001
2-Fluoro-phenylamine (2g, 0.018mol) were added to a solution of selectfluor reagent (5.9g, 0.017mol) and KSCN (1.81g, 0.019mol) in acetonitrile and the resulting reaction mass was stirred for 70hrs at RT. The solvent was distilled and the reaction mass was dissolved in water (30OmL), extracted twice with DCM (75mL) and the organic layer was washed with water (10OmL) and brine solution (10OmL). The reaction mixture was dried over Na2SO4, concentrated and the concentrate was purified by column chromatography (using silica gel, 5-10% of ethylacetate in hexane as eluant) to afford 740mg (25% yield) of 2-fluoro-4-thiocyanato-phenylamine as a pale yellow liquid. 1H NMR (DMSO-D6, 300 MHz): δ 7.3-7.15 (m, 2H), 6.8 (t, IH), 4.15-4.0 (br s, 2H)
Step: 3b
Synthesis of 2-Fluoro-4-methylsulfanyl-phenylamine.
Figure imgf000094_0001
Na2S (1.04g, 0.01 lmol) in water (2.2mL) was added to a solution of 2-fluoro-4- thiocyanato-phenylamine (730mg, 0.004mol) in ethanol (12mL) and the reaction mixture was stirred for 2hrs at 5O0C. This was followed by addition of CH3I (683mg, 0.0047mol) in ethanol (2mL) and the stirring was continued for a further 3hrs. The reaction mass was diluted with ethylacetate, this was followed by addition of water (5OmL) and extraction with ethylacetate.. The organic layer was washed with water (2OmL), brine solution (2OmL) and concentrated to afford 610mg (89% yield) of 2- fluoro-4-methylsulfanyl-phenylamine as the required product.
1H NMR (DMSO-D6, 300 MHz): δ 7.2-6.92 (m, 2H), 6.72 (t, IH), 3.8-3.6 (br s, 2H), 2.4 (s, 3H)
Step: 4
Synthesis of 6-Fluoro-7-(2-fluoro-4-methylsulfanyl-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid.
Figure imgf000094_0002
LDA (316mg, 0.00296mol) was added to a solution of 2-fluoro-4-methylsulfanyl- phenylamine (322mg, 0.002mol) in THF (1OmL) at -780C and the resulting mixture was stirred for 1.30hrs at -780C. This was followed by addition of 7-chloro-6-fluoro-5- oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (190mg, O.OOlmol) in THF (3OmL) at -780C and the stirring was continued for a further 24hrs at RT. THF was distilled from the reaction mixture and this was followed by addition of IN HCl (12mL) and ether (1OmL). The reaction mixture was stirred for 15 minutes and the precipitate was collected to afford 128mg of 6-fluoro-7-(2-fluoro-4-methylsulfanyl-phenylamino)-5- oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid along with the starting material which was used in the next step without further purification. LC-MS purity: 50%, m/z =353, (M+)
Step: 5
Synthesis of 6-Fluoro-7-(2-fluoro-4-methylsulfanyl-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000095_0001
EDCI (227mg, 0.00 lmol) and HOBt (160mg, 0.00 lmol) were added to a stirred solution of 6-fluoro-7-(2-fluoro-4-methylsulfanyl-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (120mg, 0.0003mol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O- cyclopropylmethyl-hydroxylamine hydrochloride (147mg, O.OOlmol) and TEA (120mg, O.OOlmol). The reaction mixture was stirred for 16 hrs at RT. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCOs, NH4Cl, brine solution, dried over Na2SO4 and concentrated. The concentrate was dissolved in methanol (0.5mL) and diethyl ether (1OmL). The precipitate was collected to afford 7mg (9.8% yield) of 6-fluoro-7-(2-fluoro-4- methylsulfanyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide as the required product. LCMS purity: 89.5%, m/z=422, (M+) HPLC: 91%
1H NMR (DMSO-D6, 300 MHz): δ 11.4 (s, IH), 8.0 (s, IH), 7.2 (d,lH), 7.0 (s, 2H), 4.0 (t, 2H), 3.5 (d, 2H), 3.2 (t, 2H), 2.5 (s, 3H), 2.14-2.04 (m, 2H), 1.05-0.95 (m, IH), 0.55- 0.45 (m, 2H), 0.25-0.15 (m, 2H).
Example: 50 Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 11. Scheme: 9
Figure imgf000096_0001
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid pentafluorophenyl ester.
Figure imgf000096_0002
2,3,4,5,6-Pentafluoro-benzoic acid trifluoromethyl ester (136mg, 0.0005mol) and pyridine (38mg, 0.0005mol) were added to a solution of 7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (170mg, 0.0004mol) in DMF (3mL) and the reaction mixture was stirred for 4hrs at RT. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with NaHCCh, twice with IM HCl solution and brine solution. The organic layer was dried over Na2SO4 and concentrated to afford 256mg of 7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid pentafluorophenyl ester as the crude product which was used for the next step without further purification.
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid hydrazide.
Figure imgf000097_0001
TEA (98mg, O.OOlmol) was added to a stirred solution of hydrazine hydrochloride (35mg, O.OOlmol) in DCM (5mL) and the reaction mixture was stirred for lhr. This was followed by addition of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid pentafluorophenyl ester (251mg, 0.0005mol) and the stirring was continued for a further 8hrs. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed twice with water, saturated NaHCO3 and twice with brine solution. The organic layer was dried over Na2SO4 and concentrated to afford 138mg (55% yield) of 7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo- 1 ,2,3 ,5-tetrahydro-indolizine-8-carboxylic acid hydrazide as the required product. LCMS purity: 78%, m/z=399, 401, (M+)
Step: 6a
Synthesis of 2-(tert-Butyl-dimethyl-silanyloxy)-ethylamine.
Figure imgf000097_0002
Imidazole (23.4g, 0.344mol) was added to a solution of 2-amino-ethanol (2Og, 0.327mol) in DMF (40OmL) and the reaction mixture was cooled to O0C. This was followed by addition of tert-butyl-chloro-dimethyl-silane (51.8g, 0.344mol) and the reaction mixture was stirred for 3hrs at RT. The residual mass was diluted with water (IL) and extracted twice with ethylacetate (30OmL). Ethyl acetate layer was washed with water, 0.1N HCl (10OmL) and brine solution (10OmL). The organic layer was dried over Na2SO4, concentrated and the crude product was purified by column chromatography (using silica gel, 30-40% ethylacetate in hexane as the eluting system) to afford 18. Ig (31% yield) of 2-(tert-butyl-dimethyl-silanyloxy)-ethylamine as the required product. LCMS purity: 92%, m/z=176, (M+)
Step: 6b
Synthesis of Imidazole-1-carboxylic acid [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]- amide.
Figure imgf000098_0001
2-(tert-Butyl-dimethyl-silanyloxy)-ethylamine (7.3g, 0.042mol) in DCM (15OmL) was added to a solution of CDI (10. Hg, 0.062mol) in THF (6OmL) at RT and the reaction mixture was stirred for 8hrs at 5O0C. The solvent from the reaction mixture distilled and the residual crude product was purified by column chromatography (using silica gel , 20-40% ethylacetate in hexane as the eluting system) to afford 2.1g (19% yield) of imidazole-1-carboxylic acid [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amide as the required product. LCMS purity: 94.5%, m/z=270, (M+)
Step: 7
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid N'-2-(tert-Butyl-dimethyl-silanyloxy)-ethyl-amino- carbonyl-hydrazide.
Figure imgf000098_0002
Acetic acid (63mg, 0.0003mol) and 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, S-tetrahydro-indolizine-S-carboxylic acid hydrazide (135mg, 0.0003mol) were added to a solution of imidazole- 1-carboxy lie acid [2-(tert-butyl-dimethyl-silanyloxy)- ethyl] -amide (91mg, 0.0003mol) in THF (1OmL) and the reaction mixture was stirred for 14hrs at RT. The solvent from the reaction mixture was distilled to afford 213mg of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid N'-2-(tert-butyl-dimethyl-silanyloxy)-ethyl-amino-carbonyl-hydrazide as the crude product which was used for the next step without a further purification. LCMS purity: 49%, m/z=600, (M+)
Step: 8
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-8- {5- [2-(tert-butyl-dimethyl- silanyloxy)-ethylamino]-[l,3,4]oxadiazol-2-yl}-6-fluoro-2,3-dihydro-lH-indolizin-
5-one.
Figure imgf000099_0001
Tosyl chloride (63mg, 0.0003mol) and TEA (84mg, 0.0008mol) were added to stirred a solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid N'-2-(tert-butyl-dimethyl-silanyloxy)-ethyl-amino- carbonyl-hydrazide (200mg, 0.0003mol) in DCM (8mL) and the reaction mixture was stirred for 12hrs at RT. DCM from the reaction mixture was distilled and the residual mixture was diluted with water and extracted with ethylacetate. The organic layer was dried over Na2SO4 concentrated to afford 18. Ig (31% yield) of 7-(4-bromo-2-fluoro- phenylamino)-8-{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-[l,3,4]oxadiazol-2- yl}-6-fluoro-2,3-dihydro-lH-indolizin-5-one as the crude product which was used for the next step without a further purification.
Step: 9
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8- [5-(2-hydroxy- ethylamino)-[l,3,4]oxadiazol-2-yl]-2,3-dihydro-lH-indolizin-5-one.
Figure imgf000100_0001
Acetic acid (25mg, 0.0004mol) and tetra butyl ammonium fluoride (168mg, O.OOOβmol) were added to a solution of 7-(4-bromo-2-fluoro-phenylamino)-8-{5-[2- (tert-butyl-dimethyl-silanyloxy)-ethylamino]-[l,3,4]oxadiazol-2-yl}-6-fluoro-2,3- dihydro-lH-indolizin-5-one (250mg, 0.0004mol) in THF (6mL) at O0C and the reaction mixture was stirred for 3hrs at RT. The reaction mixture was diluted with ethylacetate and water. The organic layer was washed with NaHCOs solution, IM HCl and brine solution, dried over Na2SO4 and concentrated. The crude product was dissolved in DCM (2mL), this was followed by addition of diethyl ether, the precipitate formed was collected and dried to afford 27.5mg (14% yield) of 7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-8-[5-(2-hydroxy-ethylamino)-[l,3,4]oxadiazol-2-yl]-2,3- dihydro-lH-indolizin-5-one as the required product. LCMS purity: 92.2%, m/z=468, 470 (M+) HPLC: 95%
1H NMR (DMSO-D6, 300 MHz): δ 9.1 (s, IH), 7.82 (t, IH), 7.55 (d,lH), 7.32 (s, IH), 7.12 (m, IH), 4.8 (t, IH), 4.1 (t, 2H), 3.6-3.5 (q, 12H), 3.4-3.2 (m, 4H), 2.3-2.1 (m, 2H).
Example: 51
Steps 1 to 4 were performed in a manner similar to what has been described for example 8
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxy-amide.
Figure imgf000100_0002
EDCI (296mg, 0.0015mol) and HOBt (209mg, 0.0015mol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0005mol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O-methyl- hydroxylamine (130mg, 0.002mol) and TEA (156mg, 0.002mol). The reaction mixture was stirred for 19 hrs at RT. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCOs, saturated NH4Cl, and brine solution, dried over Na2SO4 and concentrated. The concentrate was dissolved in IPA (2mL), this was followed by the addition of diethyl ether (15mL).The precipitate formed was collected to afford 57mg (27% yield) of 7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo- 1 ,2,3 ,5-tetrahydro-indolizine-8-carboxylic acid methoxy- amide as the required product. LCMS purity: 97%, m/z 413,415 (M+, Br pattern) HPLC: 99%
1H NMR (DMSO-D6, 300 MHz): δ 11.42 (s, IH), 8.1 (s, IH), 7.5 (d, IH), 7.3(d, IH), 6.98 (m, IH), 4.00 (t, 2H), 3.6(s, 3H), 3.3(t, 2H), 2.10 (m, 2H)
Example: 52
Steps 1 to 4 were performed in a manner similar to what has been described for example 8
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethoxy-amide.
Figure imgf000101_0001
EDCI (296mg, 0.002mol) and HOBt (209mg, 0.002mol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (200mg, 0.0005mol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O-ethyl- hydroxylamine (152mg, 0.002mol) and TEA (156mg, 0.002mol). The reaction mixture was stirred for 18 hrs at RT. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO3, saturated NH4C1, and brine solution, dried over Na2SO4 and concentrated. The concentrate was dissolved in methanol (ImL), ether (1OmL) was added to this and the precipitate formed was collected to afford 97mg (44% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5- oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethoxy-amide as the required product.
LCMS purity: 97%, m/z 428,430 (M+, Br pattern)
HPLC: 97.6%
1H NMR (DMSO-D6, 300 MHz): δ 11.4 (s, IH), 8.08 (s, IH), 7.52 (d, IH), 7.28 (d,
IH), 6.98 (m, IH), 4.00 (t, 2H), 3.8 (q, 2H), 3.2 (t, 2H), 2.10 (m, 2H), 1.12 (t, 3H)
Example: 53
Steps 1 to 4 were performed in a manner similar to what has been described for example 8
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-vinyloxy-ethoxy)-amide.
Figure imgf000102_0001
EDCI (148mg, O.OOlmol) and HOBt (104mg, O.OOlmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (lOOmg, 0.0003mol) in DMF (3mL) and the reaction mixture was stirred for 1.30hr at RT. This was followed by addition of O-(2-vinyloxy- ethyl)-hydroxylamine (80mg, O.OOlmol) and TEA (78mg, O.OOlmol). The reaction mixture was stirred for 19 hrs at RT. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCOs, saturated NH4Cl, and brine solution, dried over Na2SO4 and concentrated to afford HOmg of the crude product which was used in the next step without a further purification.
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
Figure imgf000103_0001
IN HCl (1.6mL) were added to a stirred solution of 7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo- 1 ,2,3 ^-tetrahydro-indolizine-S-carboxylic acid (2- vinyloxy-ethoxy)-amide (HOmg, 0.0002mol) in a 1 :1 mixture of THF and EtOH (2mL). The reaction mixture was stirred for lhr. The reaction mixture was diluted with ethylacetate; pH was adjusted to 5 using 2N NaOH and extracted with EtOAc.
The organic layer was dried over Na2SO4 and concentrated. The concentrate was dissolved in 2mL of IPA, 1OmL of ether was added to this and the precipitate formed was collected to afford 8mg (7% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro- 5-oxo-l,2,3, 5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide as the required product.
LCMS purity: 91.8%, m/z=443.9, 445.9 (M+, Br pattern) HPLC: 98.2%
1H NMR (DMSO-D6, 300 MHz): δ 11.42 (s, IH), 8.1 (s, IH), 7.5 (d, IH), 7.3 (d, IH), 6.98 (m, IH), 4.8 (t, IH), 4.00 (t, 2H), 3.8 (t, 2H) 3.55 (t, 2H), 3.2 (t, 2H), 2.12 (m, 2H)
Example: 54
Steps 1 to 3 were performed in a manner similar to what has been described for example 8
Step: 4
Synthesis of 7-(4-Bromo-2-methyl-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid.
Figure imgf000103_0002
LDA (2.33g, 0.01 lmol) was added to a solution of 4-bromo-2-methyl-phenylamine (1.4mg, 0.008mol) in THF (1OmL) at -780C and the resulting mixture was stirred for lhr at -780C. This was followed by addition of 7-chloro-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (700mg, 0.003mol) in THF (5OmL) at -780C and the stirring was continued for a further 20hrs at RT. THF was distilled and this was followed by addition of IN HCl (2OmL), water (25mL) and ether (1OmL). The precipitate formed was collected to afford 281mg (24% yield) of 7-(4-bromo-2-methyl- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid.
LCMS purity: 96%, m/z 380, 382 (M+, Br Pattern)
HPLC: 95.89%
1H NMR (DMSO-D6, 300MHz): δ 13.70 (s, IH), 9.4 (s, IH), 7.4 (s, IH), 7.3 (d, IH),
6.8 (m, IH), 4.04 (t, 2H), 3.48 (t, 2H), 2.25 (s, 3H), 2.10 (m, 2H).
Example: 55
Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 54.
Step: 5
Synthesis of 7-(4-Bromo-2-methyl-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000104_0001
EDCI (346mg, 0.002mol) and HOBt (244mg, 0.002mol) were added to a stirred solution of 7-(4-bromo-2-methyl-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (230mg, O.OOlmol) in DMF (3mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O- cyclopropylmethyl-hydroxylamine (224mg, 0.002mol) and TEA (183mg, 0.002mol). The reaction mixture was stirred for 24 hrs at RT. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCOs, saturated NH4C1, and brine solution, dried over Na2SO4 and concentrated. The concentrate was dissolved in 5mL of methanol, 25mL of diethyl ether was added into this and the precipitate formed was collected to afford 40mg (14.7% yield) of 7-(4- bromo-2-methyl-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide as the required product. LCMS purity: 95%, m/z 450,452 (M+, Br pattern) HPLC: 96.1% 1H NMR (DMSO-D6, 300MHz): δ 11.30 (s, IH), 7.78 (s, IH), 7. 4 (s, IH), 7.22 (d, IH), 6.88 (m, IH), 4.00 (t, 2H), 3.4 (d, 2H), 3.20 (t, 2H), 2.2 (s, 3H) 2.10 (m, 2H), 1.00 (m, IH), 0.50 (m, 2H), 0.20 (m, 2H)
Example: 56
Steps 1 to 3 were performed in a manner similar to what has been described for example 8
Step: 4
Synthesis of 7-(4-Bromo-2-methyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid.
Figure imgf000105_0001
LDA (2.7g, 0.0253mol) were added to a solution of 4-bromo-2-methyl-phenylamine (3.28mg, 0.018mol) in THF (3OmL) at -780C and the resulting mixture was stirred for 45mins at -780C. This was followed by addition of 7-chloro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (1.5g, O.Olmol) in THF (9OmL) at -780C and the stirring was continued for a further 21hrs at RT. THF was distilled and this was followed by addition of 6OmL of IN HCl (pH=l), water (115mL) and diethylether (115mL). The precipitate formed was collected to afford 610mg (36% yield) of 7-(4-bromo-2-methyl- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid. LCMS purity: 93%, m/z 363,365(M+, Br Pattern) HPLC: 95.3%
1H NMR (DMSO-D6, 300 MHz): δ 13.30 (s, IH), 9.8 (s, IH), 7.6 (s, IH), 7.42 (d, IH), 7.2 (m, IH), 5.08 (s, IH), 3.8 (t, 2H), 3.48 (t, 2H), 2.35 (s, 3H), 2.15 (m, 2H).
Example: 57
Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 56.
Step: 5
Synthesis of 7-(4-Bromo-2-methyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000106_0001
EDCI (473mg, 0.002mol) and HOBt (334mg, 0.002mol) were added to a stirred solution of 7-(4-bromo-2-methyl-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid (300mg, O.OOlmol) in DMF (3mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of O-cyclopropylmethyl- hydroxylamine (306mg, 0.002mol) and TEA (250mg, 0.002mol). The reaction mixture was stirred for 26 hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NH4Cl, saturated NaHCOs solution and brine solution, dried over Na2SO4 and concentrated. The concentrate was dissolved in 2.5mL of methanol, 1OmL of diethyl ether was added into this and the precipitate formed was collected to afford 47mg (13% yield) of 7-(4-Bromo-2-methyl- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide as the required product. LCMS purity: 96%, m/z 432,434 (M+, Br pattern) HPLC: 92.1%
1H NMR (DMSO-D6, 300 MHz): δ 11.36 (s, IH), 8.02 (s, IH), 7. 58 (s, IH), 7.4 (d, IH), 7.15 (m, IH), 5.02 (s, IH) 3.8 (t, 2H), 3.7 (d, 2H), 3.20 (t, 2H), 2.2 (s, 3H) 2.16 (m, 2H), 1.10 (m, IH), 0.52 (m, 2H), 0.30 (m, 2H)
Example: 58
Steps 1 to 4 were performed in a manner similar to what has been described for example 8
Step: 5
Synthesis of 2-{l-[6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carbonyl]-3-hydroxy-azetidin-3-yl}-piperidine-l- carboxylic acid tert-butyl ester.
Figure imgf000107_0001
EDCI (154mg, O.OOlmol) and HOBt (lOOmg, O.OOlmol) were added to a stirred solution of 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (140mg, 0.0003mol) in DMF (4mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of 2-(3-hydroxy- azetidin-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (S-isomer) (166mg, O.OOlmol) and TEA (98mg, O.OOlmol). The reaction mixture was stirred for 16 hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NH4Cl, saturated NaHCOs solution and brine solution, dried over Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel , 2-3% methanol in DCM as eluant) to afford 180mg (82.9% yield) of 2-{l-[6-fiuoro-7-(2-fiuoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carbonyl]-3-hydroxy-azetidin-3-yl} -piperidine- 1 -carboxylic acid tert-butyl ester (S-isomer) as the required product.
Step: 6
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-8-(3-hydroxy-3-piperidin-
2-yl-azetidine-l-carbonyl)-2,3-dihydro-lH-indoIizin-5-one hydrochloride.
Figure imgf000107_0002
4N Dioxane in HCl (2.5mL) were added to a solution of 2-{l-[6-fluoro-7-(2-fluoro-4- iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indo lizine-8-carbonyl]-3-hydroxy- azetidin-3-yl} -piperidine- 1 -carboxylic acid tert-butyl ester (S-isomer) (50mg, 0.0001 mo 1) in methanol (2mL) and the resulting mixture was stirred for lhr at RT. The solvents were distilled from the reaction mixture and the residue was triturated with ether to afford 34mg (75% yield) of 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-8-(3- hydroxy-3 -piperidin-2-yl-azetidine- 1 -carbonyl)-2 ,3 -dihydro- 1 H-indo lizin-5 -one hydrochloride (S-isomer) as the required product. LCMS purity: 95.5%, m/z=570.9 (M+) HPLC: 91.6%
1H NMR (DMSO-D6, 300 MHz): δ 8.4-8.2 (br s, IH), 8.1 (s, IH), 7.6 (d, IH), 7.4 (d, IH), 7.02-6.92 (m, IH), 4.2-4.1 (m, IH), 4.10-3.95 (m, 3H), 3.9-3.8 (m, IH), 3.75-3.65 (m, IH), 3.5-3.45 (m, IH), 3.2-3.1 (m, 2H), 3.08 (t, 2H), 2.9-2.8 (m, IH), 2.2-2.08 (m, 2H), 1.75-1.65 (m, 4H), 1.5-1.35 (m,2H)
Example: 59
Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 11.
Step: 5
Synthesis of 2-{l-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carbonyl]-3-hydroxy-azetidin-3-yl}-piperidine-l- carboxylic acid tert-butyl ester.
Figure imgf000108_0001
EDCI (185mg, O.OOlmol) and HOBt (131mg, O.OOlmol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid (250mg, O.OOlmol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of 2-(3-hydroxy- azetidin-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (racemic mixture) (199mg, O.OOlmol) and TEA (196mg, 0.002mol). The reaction mixture was stirred for 16 hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NH4Cl (1OmL), saturated NaHCO3 solution (1OmL) and brine solution (1OmL), dried over Na2SO4 and concentrated. The concentrate was dissolved in 3mL of ethylacetate to yield a precipitate which was collected to afford 200mg (49.6% yield) of 2-{l-[7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carbonyl]-3-hydroxy-azetidin-3-yl}-piperidine-l- carboxylic acid tert-butyl ester (racemic mixture) as the required product. HPLC: 98.4%
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(3-hydroxy-3- piperidin-2-yl-azetidine-l-carbonyl)-2,3-dihydro-lH-indolizin-5-one.
Figure imgf000109_0001
4N Dioxane in HCl (4mL) were added to a solution of 2-{l-[7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8-carbonyl]-3-hydroxy- azetidin-3-yl}-piperidine-l-carboxylic acid tert-butyl ester (racemic mixture) (75mg, O.OOOlmol) in methanol (ImL) and the resulting mixture was stirred for lhr at RT. The solvents were distilled from the reaction mixture. Trituration with 5mL of diethyl ether affords a precipitate which was collected to afford 48mg (71.6% yield) of 7-(4-bromo- 2-fluoro-phenylamino)-6-fluoro-8-(3-hydroxy-3-piperidin-2-yl-azetidine-l-carbonyl)- 2,3-dihydro-lH-indolizin-5-one (racemic mixture) as the required product. LC-MS purity: 97%, m/z 523, 525 (M+, Br Pattern) 1H NMR (DMSO-D6): δ 8.3-8.2 (br s, IH), 8.12 (s, IH), 7.52 (d,lH), 7.3 (d, IH), 7.16-
7.02 (m, IH), 4.2-4.1 (m, IH), 4.10-3.90 (m, 4H), 3.75-3.65 (m, IH), 3.5-3.45 (m, IH), 3.2-3.1 (m, 2H), 3.08 (t, 2H), 2.9-2.8 (m, IH), 2.2-2.08 (m, 2H), 1.8-1. 5 (m, 4H), 1.45-
1.3 (m, 2H)
Example: 60
Steps 1 to 4 were performed in a manner similar to what has been described for example 8
Step: 5 Synthesis of 2-{l-[6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carbonyl]-3-hydroxy-azetidin-3-yl}-piperidine-l- carboxylic acid tert-butyl ester.
Figure imgf000110_0001
EDCI (165mg, O.OOlmol) and HOBt (178mg, O.OOlmol) were added to a stirred solution of 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (250mg, O.OOlmol) in DMF (5mL) and the reaction mixture was stirred for lhr at RT. This was followed by addition of 2-(3-hydroxy- azetidin-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (racemic mixture) (180mg, O.OOlmol) and TEA (175mg, 0.002mol). The reaction mixture was stirred for 16 hrs at RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NH4Cl (1OmL), saturated NaHCOs solution (1OmL) and brine solution (1OmL), dried over Na2SO4 and concentrated. The concentrate (lOOmg) was used for the next step without further purification.
Step: 6
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-8-(3-hydroxy-3-piperidin-
2-yl-azetidine-l-carbonyl)-2,3-dihydro-lH-indoIizin-5-one.
Figure imgf000110_0002
4N Dioxane in HCl (5mL) was added to a solution of 2-{l-[6-fluoro-7-(2-fluoro-4- iodo-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8-carbonyl]-3-hydroxy- azetidin-3-yl}-piperidine-l-carboxylic acid tert-butyl ester (racemic mixture) (lOOmg, O.OOOlmol) in methanol (ImL) and the resulting mixture was stirred for lhr at RT. The solvents were distilled from the reaction mixture to yield a precipitate which was purified by preparative HPLC to afford 15mg (16.6% yield) of 6-fluoro-7-(2-fluoro-4- iodo-phenylamino)-8-(3-hydroxy-3-piperidin-2-yl-azetidine-l-carbonyl)-2,3-dihydro- lH-indolizin-5-one (racemic mixture) as the required product. LC-MS purity: 95%, m/z 571 (M+)
1H NMR (DMSO-D6): δ 8.6-8.4 (br s, IH), 8.2 (s, IH), 7.6 (d,lH), 7.44 (d, IH), 6.98- 6.9 (m, IH), 4.2-4.1 (m, IH), 4.10-3.95 (m, 3H), 3.9-3.8 (m, IH), 3.75-3.65 (m, IH), 3.5-3.45 (m, IH), 3.2-3.1 (m, 2H), 3.08 (t, 2H), 2.9-2.8 (m,lH), 2.2-2.08 (m, 2H), 1.75- 1.65 (m, 4H), 1.5-1.35 (m, 2H)
Example: 61 Scheme: 10*
Figure imgf000111_0001
* in Step 8 B must be 2.
Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 11.
Step: 5 Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-4-fluoro-l,6,7,8-tetrahydro-3H-l,3,5a- triaza-as-indacene-2,5-dione.
Figure imgf000112_0001
TEA (0.12mL, O.OOlmol) and DPPA (0.18mL, O.OOlmol) were added to a solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (300mg, O.OOlmol) in DMF (5mL) and the reaction mixture was stirred for 4hrs at RT under nitrogen atmosphere. This was followed by addition of toluene (5mL) and the reaction mixture was heated to 9O0C for 2hrs. The reaction mixture was concentrated under reduced pressure, added water to yield a precipitate which was collected and dried to afford 250mg (84% yield) of 3-(4-bromo-2-fluoro- phenyl)-4-fluoro- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a-triaza-as-indacene-2,5-dione as the required product.
Step: 6
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-l-cyclopropanesulfonyl-4-fluoro-l,6,7,8- tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione.
Figure imgf000112_0002
60% NaH (30mg, O.OOlmol) were added to a stirred solution of 3-(4-bromo-2-fluoro- phenyl)-4-fluoro-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (0.2g,
O.OOlmol) in dry DMF (4mL) at 0-50C under nitrogen atmosphere and the resulting mixture was stirred for lhr at RT. This was followed by dropwise addition of cyclopropanesulfonyl chloride (1 lOmg, O.OOlmol) in dry THF over a period of lOmins at O0C and the stirring was continued for the next 16hrs at RT. The crude product was used for the next step without a further purification.
Step: 7 Synthesis of Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6- fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000113_0001
IN aqueous NaOH (6mL) were added to 3-(4-bromo-2-fluoro-phenyl)-l- cyclopropanesulfonyl-4-fluoro-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5- dione and the resulting mixture was heated to 650C for 4hrs. Ice cold water was added to the reaction mixture, neutralized with 5% ice cold HCl to pH of about 4 and the reaction mixture was partitioned between ethylacetate and water. The organic layer was dried over Na2SO4, concentrated under reduced pressure and the concentrate was purified by column chromatography (using silica gel, 2% methanol in DCM as eluant) to afford 21mg (8.5% yield) of cyclopropanesulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide as the required product.
LCMS purity: 98.89%, m/z=461.9 (M+)
HPLC: 93.6%
1H NMR (DMSO-D6, 300 MHz): δ 8.9 (s, IH), 7.65-7.25 (m, 3H), 4.1 (t, 2H), 3.2 (t,
2H), 2.8-2.7 (m,lH), 2.2-2.1 (m, 2H), 0.95-0.85 (m, 4H)
Example: 62
Steps 1 to 4 were performed in a manner similar to what has been described for example 8 and step 5 was performed in a manner similar to what has been described for example 61
Step: 6
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-4-fluoro-2,5-dioxo-2,3,5,6,7,8- hexahydro-l,3,5a-triaza-as-indacene-l-carboxylic acid tert-butyl ester.
Figure imgf000113_0002
60% NaH (0.4g, O.Olmol) were added to a stirred solution of 3-(4-bromo-2-fluoro- phenyl)-4-fluoro-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (2.5g,
0.007mol) in dry DMF (2OmL) at RT under nitrogen atmosphere. The resulting mixture was stirred for 30mins. This was followed by dropwise addition of BOC anhydride (1.9g, 0.009mol) in dry THF over a period 5mins of at O0C and the reaction mixture was stirred for 4hr at RT. The crude product was used in the next step without further purification.
Step: 7
Synthesis of [7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizin-8-yl]-carbamic acid tert-butyl ester.
Figure imgf000114_0001
IN aqueous NaOH (15mL) were added to 3-(4-bromo-2-fluoro-phenyl)-4-fluoro-2,5- dioxo-2,3,5,6,7,8-hexahydro-l,3,5a-triaza-as-indacene-l-carboxylic acid tert-butyl ester at O0C and the resulting mixture was stirred at RT for 6hrs. The reaction mass was extracted with ethylacetate. The organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure to afford 1.15g (28% yield) of [7-(4- bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]- carbamic acid tert-butyl ester as the required product.
1HNMR (CDCl3, 300MHz): δ 7.45-6.7 (m, 3H), 6.1 (s, IH), 5.65 (s, IH), 4.25 (t, 2H), 3.15 (t, 2H), 2.25-2.0 (m, 2H), 1.45 (s, 9H).
Step: 8
Synthesis of 8-Amino-7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-2,3-dihydro- lH-indolizin-5-one.
Figure imgf000114_0002
IN cone. HCl (4mL) were added to a stirred solution of [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-carbamic acid tert- butyl ester (0.9g, 0.002mol) in THF (1OmL) and the reaction mixture was stirred for 4 hrs at RT. The reaction mixture was concentrated under reduced pressure, added saturated NaHCO3 solution and extracted with ethylacetate. The organic layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 360mg (72% yield) of 8-amino-7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-2,3-dihydro-lH- indolizin-5-one as the required product.
1HNMR (DMSO, 300MHz): δ 7.85-6.85 (m, 3H), 4.2 (s, 2H), 4.12 (t, 2H), 3.1 (t, 2H), 2.25-2.0 (m, 2H)
Step: 9
Synthesis of N-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizin-8-yl]-N,N-dimethyl-amino-sulfonamide.
Figure imgf000115_0001
Pyridine (2mL) were added to a solution of 8-amino-7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-2,3-dihydro-lH-indolizin-5-one (200mg, O.OOlmol) and the reaction mixture was stirred for 5mins under nitrogen atmosphere. This was followed by addition of DMAP (5mg, 0.0004mol), cooled the reaction mass to O0C, added N5N- dimethyl-sulfonyl chloride (85mg, O.OOlmol) and continued stirring for next 16hrs at RT. The reaction was monitored by TLC (100% ethylacetate) which showed the presence of starting material. The reaction mixture was heated to 5O0C for 2hrs. The reaction mixture was partitioned between ethylacetate (3x50mL) and water. The organic layer was washed with saturated NH4Cl solution, dried over Na2SO4, concentrated under reduced pressure and the concentrate was purified by column chromatography (using neutral alumina, ethylacetate as eluant) to afford 22mg (8% yield) of N-[7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizin-8-yl]-N,N-dimethyl-amino-sulfonamide as the required product. LCMS purity: 96.189%, m/z = 463 (M+) HPLC: 98% 1H NMR (DMSO-D6, 300 MHz): δ 8.7 (s, IH), 7.6-6.85 (m, 3H), 4.15 (t, 2H), 3.29 (t, 2H), 2.7 (s, 6H), 2.2-2.1 (m, 2H)
Example: 63
Steps 1 to 4 were performed in a manner similar to what has been described for example 8, step 5 was performed in a manner similar to what has been described for example 61 and steps 6 to 8 were performed in a manner similar to what has been described for example 62,
Step: 8a
Synthesis of N-(2,2-Dimethyl-[l,3]dioxolan-4-ylmethyl)-chloro-sulfonamide.
Figure imgf000116_0001
C-(2,2-Dimethyl-[l,3]dioxolan-4-yl)-methylamine (300mg, 0.00229mol) and DMAP (295mg, 0.0024mol) in dry DCM were added to a stirred solution of sulfuryl chloride (320mg, 0.0023mol) in DCM at -780C and the resulting mixture was stirred at -780C for lhr, at -5O0C for 2hrs and at RT for 2hrs. The product formed was used for next step.
Step: 9
Synthesis of N-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizin-8-yl] -C-(2,2-Dimethyl- [ 1 ,3] dioxolan-4-yl)-methylamine- sulfonamide.
Figure imgf000116_0002
N-(2,2-Dimethyl-[l,3]dioxolan-4-ylmethyl)-chloro-sulfonamide (0.001 mol) was added dropwise to a stirred solution of 8-amino-7-(4-bromo-2-fluoro-phenylamino)-6-fluoro- 2,3-dihydro-lH-indolizin-5-one (200mg, O.OOlmol) in dry pyridine (3mL) and DMAP (50mg, 0.0004mol) over a period of lOmins at O0C and the reaction mixture was heated to 4O0C for 16hrs The reaction mixture was concentrated under reduced pressure and the concentrate was partitioned between ethylacetate and water. The organic layer was concentrated and the concentrate was purified by column chromatography (using neutral alumina, DCM as eluant) to afford 26mg (5% yield) of N-[7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-o xo- 1,2,3, 5-tetrahydro-indolizin-8-yl]-C-(2,2-dimethyl- [l,3]dioxolan-4-yl)-methylamine-sulfonamide as the required product. 1H NMR (DMSO, 300MHz): δ 8.7 (s, IH), 7.6-6.7 (m, 3H), 4.1-3.8 (m, 4H), 3.65-3.5 (m, IH), 3.3-3.2 (m, IH), 3.2 (t, 2H), 3.1-2.9 (m, IH), 2.9-2.6 (m, IH), 2.1 (t, 2H), 1.2 (d, 6H)
Step: 10
Synthesis of 2,3-Dihydroxy-propane-amino-sulfonicacid- [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000117_0001
Cone. HCl (ImL) were added to a stirred solution of N-[7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-C-(2,2-Dimethyl- [l,3]dioxolan-4-yl)-methylamine-sulfonamide (26mg, 0.00005mol) in ethanol (4mL) at 2O0C and the reaction mixture was stirred for 4 hrs at RT. The reaction mixture was concentrated under reduced pressure, added diethyl ether, decanted and dried under reduced pressure to afford 16mg (70% yield) of 2,3-dihydroxy-propane-amino- sulfonicacid-[7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizin-8-yl]-amide as the required product. LCMS purity: 97.1%, m/z = 509 (M+) HPLC: 96.8%
1H NMR (DMSO-D6, 300 MHz): δ 8.7 (s, IH), 7.6-6.85 (m, 3H), 4.15 (t, 2H), 3.4 (t, 2H), 3.25-3.15 (m, 2H), 3.1-3.0 (m, 2H), 2.85-2.75 (m, IH)
Example: 64
Steps 1 to 4 were performed in a manner similar to what has been described for example 8, step 5 was performed in a manner similar to what has been described for example 61 and steps 6 to 8 were performed in a manner similar to what has been described for example 62.
Scheme: 11
Figure imgf000118_0001
Step: 8a
Synthesis of Pyrrolidine-2-carboxylic acid benzyl ester hydrochloride
Figure imgf000118_0002
Thionyl chloride (8mL) and pyrrolidine-2-carboxylic acid (3g, 0.026mol) were added to benzyl alcohol (2OmL) at -1O0C under nitrogen atmosphere and the reaction mixture was stirred at RT for 16hrs. The reaction mass was diluted with dry diethyl ether and stirred at RT for 2hrs to yield a precipitate which was washed with excess diethyl ether, decanted and dried under reduced pressure to afford 4g (66% yield) of pyrrolidine-2- carboxylic acid benzyl ester hydrochloride as the required product. 1H NMR (CDCl3, 300MHz): δ 10.9 (s, IH), 9.2 (s, IH), 7.2-7.6 (s, 5H), 5.2 (t, 2H), 4.9 (s, IH), 4.5 (s, IH), 3.5 (t, 2H), 2.4-2.3 (m, IH), 2.2-2.1 (m, 2H)
Step: 8b
Synthesis of l-Chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester
Figure imgf000118_0003
DMAP (0.5g, 0.004mol) and TEA (1.6mg, 0.016mol) were added to a stirred solution of pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (3g, 0.015mol) in dry toluene (4OmL) at RT and the resulting mixture was stirred for 20mins. The reaction mixture was cooled to -1O0C, followed by dropwise addition of sulfuryl chloride (2g, 0.015mol) over a period of 15mins and continued stirring for 3hrs at RT. The reaction mass was quenched with saturated NH4Cl solution, extracted with DCM and the organic layer was dried over Na2SO4 and concentrated to afford 1.2g of 1- chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester as the crude product. 1H NMR (DMSO-D6, 300 MHz): δ 10.9 (s, IH), 9.2 (s, IH), 7.6-7.2 (br s, 5H), 5.2 (t, 2H), 4.9 (s, IH), 4.5 (s, IH), 3.5 (t, 2H), 2.4 (m, IH), 2.2 (m, 2H)
Step: 9
Synthesis of l-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizin-8-ylsulfamoyl]-pyrrolidine-2-carboxylic acid benzyl ester.
Figure imgf000119_0001
Pyridine (3mL) and DMAP (20mg, 0.0002mol) were added to 8-amino-7-(4-bromo-2- fluoro-phenylamino)-6-fluoro-2,3-dihydro-lH-indolizin-5-one (1 lOmg, 0.0003mol) under nitrogen atmosphere an the reaction mixture was cooled to O0C. This was followed by dropwise addition of l-chlorosulfonyl-pyrrolidine-2-carboxylic acid benzyl ester (300mg, O.OOlmol) in DCM over a period of 15mins, stirred at RT for lhr and heated to 6O0C for 16hrs. The reaction mass was concentrated under reduced pressure and the concentrate was partitioned between ethylacetate and water. The organic layer was dried over Na2SO4 and purified by column chromatography (using silica gel , 100% ethylacetate as eluant) to afford 65mg (33% yield) of l-[7-(4-bromo- 2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]- pyrrolidine-2-carboxylic acid benzyl ester as the required product. 1H NMR (DMSO-D6, 300 MHz): δ 7.4-7.15 (m, 8H), 6.85-6.75 (m, IH), 6.7-6.6 (s, IH), 5.2 (q, 3H), 4.65-4.55 (m, IH), 4.25-4.2 (m, 3H), 3.65-3.55 (m, 3H), 3.4 (t, 2H), 3.3 (t, 2H), 3.25-3.15 (m, IH), 2.4 (t, 2H), 2.2 (t, 2H), 2.15-2.05 (m, 8H)
Step: 10
Synthesis of l-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizin-8-ylsulfamoyl]-pyrrolidine-2-carboxylic acid.
Figure imgf000119_0002
LiOH solution (20mg, 0.0004mol) were added to a stirred solution of l-[7-(4-bromo-2- fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]- pyrrolidine-2-carboxylic acid benzyl ester (65mg, O.OOOlmol) in methanol: THF (2: 3) and the resulting mixture was stirred at RT for 3hrs. The reaction mass was concentrated under reduced pressure, diluted with water, neutralized with 10% HCl to a pH of about 2 and the precipitate formed was collected and dried to afford 20mg (36% yield) of l-[7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizin-8-ylsulfamoyl]-pyrrolidine-2-carboxylic acid as the required product. HPLC: 91.17%
1H NMR (DMSO-D6, 300 MHz): 12.85 (s, IH), 8.9 (s, IH), 7.6-7.2 (m, 3H), 4.3-4.2 (m, IH), 4.1 (t, 2H), 3.1 (t, 2H), 2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H)
Example: 65
Steps 1 to 4 were performed in a manner similar to what has been described for example 8, step 5 was performed in a manner similar to what has been described for example 61 and steps 6 to 8 were performed in a manner similar to what has been described for example 62.
Step: 8
Synthesis of l-Chlorosulfonyl-pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000120_0001
DMAP (0.5g, 0.00409mol) and TEA (2.54g, 0.025 lmol) were added to a stirred solution of pyrrolidine-2-carboxylic acid methyl ester hydrochloride (4g, 0.024mol) in dry toluene (5OmL) at RT and the resulting mixture was stirred for lOmins. The reaction mixture was cooled to -2O0C, followed by dropwise addition of sulfuryl chloride (3.3g, 0.024mol) over a period of 30mins and the stirring was continued for lhr at -1O0C and for a further 2hrs at RT. The reaction mass was diluted with DCM and washed with aqueous NH4Cl solution. The organic layer was, dried over Na2SO4 and concentrated to afford 1.2g (24% yield) of l-chlorosulfonyl-pyrrolidine-2-carboxylic acid methyl ester as the required product. Step: 9
Synthesis of l-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizin-8-ylsulfamoyl]-pyrrolidine-2-carboxylic acid methyl ester.
Figure imgf000121_0001
DMAP (50mg, 0.0004mol) were added to a stirred solution of 8-amino-7-(4-bromo-2- fluoro-phenylamino)-6-fluoro-2,3-dihydro-lH-indolizin-5-one (300mg, O.OOlmol) in dry pyridine (5mL) and under nitrogen atmosphere an the reaction mixture was cooled to O0C. This was followed by dropwise addition of l l-chlorosulfonyl-pyrrolidine-2- carboxylic acid methyl ester (Ig, 0.004mol) in DCM over a period of lOmins and the resulting mixture was stirred at RT for 4hrs. The reaction mixture was heated to 650C for 16hrs. The reaction mass was concentrated under reduced pressure and the concentrate was partitioned between ethylacetate and water. The organic layer was washed with brine solution, concentrated under reduced pressure and the concentrate was purified by column chromatography (using silica gel, 70% ethylacetate in hexane as eluant) to afford HOmg (24% yield) of l-[7-(4-bromo-2-fluoro-phenylamino)-6- fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-ylsulfamoyl]-pyrrolidine-2-carboxylic acid methyl ester as the required product.
Step: 10
Synthesis of 2-Hydroxymethyl-pyrrolidine-l-sulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000121_0002
NaBH4 (25mg, 0.00065mol) was added to a stirred solution of l-[7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro-indolizin-8-ylsulfamoyl]-pyrrolidine- 2-carboxylic acid methyl ester (HOmg, 0.0002mol) in dry THF (3mL) under nitrogen atmosphere and the resulting mixture was heated at 6O0C. This was followed by dropwise addition of methanol (2mL) over a period of 5mins while the temperature was maintained at 6O0C for lhr. The reaction mass was concentrated under reduced pressure, added ice cold water, neutralized with 5% dil. HCl, extracted with ethylacetate and the organic layer was dried over Na2SO4 and concentrated. The crude product was dissolved in 1 : 9 methanol: DCM, added ether and the precipitate formed was collected to afford 75 g (70% yield) of 2-Hydroxymethyl-pyrrolidine-l -sulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro-indo lizin-8- yl] -amide as the required product.
LCMS purity: 99.66%, m/z = 521 (M+2)
HPLC: 95.4%
1H NMR (DMSO-D6, 300 MHz): δ 8.7 (s, IH), 7.6-7.25 (m, 3H), 4.15 (t, 2H), 3.65 (m, IH),
3.1-3.2 (m, 4H), 2.15-2.05 (m, 2H), 1.85-1.75 (m, 4H)
Example: 66 Scheme: 12
Figure imgf000122_0001
Additionally:
Figure imgf000123_0001
Steps 1 to 3 were performed in a manner similar to what has been described for example 8 and step 4 was performed in a manner similar to what has been described for example 11.
Step: 5
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxy-methyl-amide.
Figure imgf000123_0002
EDCI (0.99g, 0.005mol) and HOBt (0.702g, 0.005mol) were added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (Ig, 0.003mol) in DMF (5OmL) and the reaction mixture was stirred for 1.30hr at RT. This was followed by addition of O,N-dimethyl-hydroxylamine hydrochloride (0.506g, 0.005mol) and TEA (2.16mL, O.Olβmol) under nitrogen atmosphere. The reaction mixture was stirred for 16 hrs at RT. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with saturated NH4Cl, brine solution, dried over anhy .Na2SO4 and concentrated to afford 0.800mg (72.7% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid methoxy-methyl-amide as the required product. LCMS purity: 96.9%, m/z = 428 (M+l)
1H NMR (DMSO-D6, 300 MHz): δ 8.0-7.95 (br s, IH), 7.5-7.4 (dd, IH), 7.3-7.2 (dd, IH), 7.0 (t, IH), 4.1-3.9 (m, 2H), 3.6 (s, 3H), 3.4 (s, 3H), 3.0-2.9 (m, 2H), 2.15-2.05 (m, 2H)
Step: 6 Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carbaldehyde.
Figure imgf000124_0001
DIBAL-H (1.0 M solution in toluene) (5.7mL, 5.7mmol) were added to a solution of 7- (4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid methoxy-methyl- amide (0.7g, 1.635mmol) in dry THF (2OmL) at -780C and the reaction mixture was stirred for 2hrs at -780C. The reaction mass was quenched with saturated NH4Cl and extracted with ethyl acetate. The aqueous layer was extracted with ethylacetate and the organic layer was washed with water, brine (10 mL), dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel, 2% methanol in DCM as eluant) to afford 0.2g, (33.16% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carbaldehyde as the required product.
1H NMR (DMSO-D6, 300 MHz): δ 9.83-9.8 (d, IH), 9.6 (d, IH), 7.6 (dd, IH), 7.4-7.3 (d, IH), 7.2-7.15 (m, IH), 4.1-4.0 (t, 2H), 3.5 (t, 2H), 2.2 (t, 2H)
Step: 7
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-but-3- enyl)-2,3-dihydro-lH-indolizin-5-one.
Figure imgf000124_0002
Allyl magnesium bromide (11.65mL, 0.011653mol) were added to a solution of 7-(4- bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carbaldehyde (0.43Og, O.OOlmol) in dry THF (1OmL) at -780C under nitrogen atmosphere. The reaction mixture was stirred for 2hrs at RT. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethylacetate. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel , 1-1.5% methanol in DCM as eluant) to afford 0.250mg (52.4% yield) of 7-(4-bromo- 2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-but-3-enyl)-2,3-dihydro-lH-indolizin-5- one as the required product.
LCMS: 84.4%, m/z = 411 (M+)
HPLC: 90%
1H NMR (DMSO-D6, 300 MHz): δ 8.2-8.1 (br s, IH), 7.6-7.5 (dd, IH), 7.3 (d, IH), 6.8-
6.7 (m, IH), 6.4 (d, IH), 5.7 (m, IH), 5.0-4.8 (m, 2H), 4.7-4.6 (d, IH), 4.0-3.9 (m, 2H),
3.1-2.9 (m, 2H), 3.0-2.9 (m, IH), 2-5-2.4 (m IH), 2.3-2.2 (m, IH), 2.1 (t, 2H).
Example: 67
Steps 1 to 3 were performed in a manner similar to what has been described for example 8, step 4 was performed in a manner similar to what has been described for example 111, and steps 5 to 6 were performed in a manner similar to what has been described for example 66.
Step: 7
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-allyl)-2,3- dihydro-lH-indolizin-5-one.
Figure imgf000125_0001
Vinyl magnesium bromide (IM solution in THF) (1.62mL, 0.002mol) were added to a solution of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carbaldehyde (O.lg, 0.0003mol) in dry THF (1OmL) at -780C under nitrogen atmosphere. The reaction mixture was stirred for 2hrs at RT. The reaction mixture was quenched with saturated NH4Cl solution at -780C and extracted with ethylacetate at RT. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by preparative HPLC to afford lOmg (9% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-8-(l- hydroxy-allyl)-2,3-dihydro-lH-indolizin-5-one as the required product. LCMS: 96.4%, m/z = 399 (M+2), 398 (M+ 1) HPLC: 98%
1H NMR (DMSO-D6, 300 MHz): δ 8.0-7.8 (br s, IH), 7.6-7.4 (d, IH), 7.6-7.3 (d, IH), 6.6 (t, IH), 6.6-6.5 (br s, IH), 5.8-6.0 (m, IH), 5.2 (d, 2H), 5.0 (d, IH), 4.0 (t, 2H), 3.1
(m, 2H), 2.1 (t, 2H). Example: 68
Steps 1 to 3 were performed in a manner similar to what has been described for example 8, step 4 was performed in a manner similar to what has been described for example 11, steps 5 to 6 were performed in a manner similar to what has been described for example 66 and step 7 was performed in a manner similar to what has been described for example 67.
Step: 8
Synthesis of 8-Acryloyl-7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-2,3-dihydro- lH-indolizin-5-one.
Figure imgf000126_0001
Dess-martin periodinane (0.582g, O.OOlmol) were added to a stirred solution of 7-(4- bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-allyl)-2,3-dihydro-lH-indolizin- 5-one (0.44Og, O.OOlmol) in DCM (1OmL) and the reaction mixture was stirred for 12hrs at RT. This was followed by addition of 0.8g of NaHCOs dissolved in 1OmL of water and 2.48g of sodium thiosulfate.5H2θ dissolved in 10ml of water and continued stirring for next 5mins. The reaction mixture was extracted with DCM and the organic layer was washed with saturated NaHCOs solution, brine, dried over anhydrous Na2SO4 and concentrated to afford 0.40Og of 8-acryloyl-7-(4-bromo-2-fluoro-phenylamino)-6- fluoro-2,3-dihydro-lH-indolizin-5-one as the crude product which was used for the next step without a further purification.
Step: 9
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-8-(2,3-dihydroxy-propionyl)-6- fluoro-2,3-dihydro-lH-indolizin-5-one.
Figure imgf000126_0002
4-Methyl-morpholine-N-oxide (0.118g, 0.001012mol) and osmium tetra oxide (0.025g, 0.000 lmol) were added to a stirred solution of 8-acryloyl-7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-2,3-dihydro-lH-indolizin-5-one (0.4g, O.OOlmol) in THF (1OmL) under nitrogen atmosphere and the resulting mixture was stirred for 2hrs at RT. The reaction mixture was partitioned between ethylacetate and water. The organic layer was dried over anhydrous Na2SO4, concentrated and the concentrate was purified by column chromatography (using silica gel , 1.5% methanol in DCM as eluant) to get a yellow solid which was further purified by preparative HPLC to afford lOmg (2.3% yield) of 7-(4-bromo-2-fluoro-phenylamino)-8-(2,3-dihydroxy-propionyl)-6-fluoro-2,3- dihydro-lH-indolizin-5-one as the required product. LCMS: m/z = 431 (M+2) HPLC: 90%
1H NMR (DMSO-D6, 300 MHz): δ 8.6-8.5 (br s, IH), 7.5-7.4 (dd, IH), 7.3-7.2 (dd, IH), 6.9-6.8 (m, IH), 5.3 (d, IH), 5.0 (t, IH), 4.5-4.4 (m, IH), 4.1-4.0 (m, 2H), 3.5 (t, 2H), 3.3-3.2 (m, IH), 3.1-3.0 (m, IH), 2.1 (t, 2H)
Example: 69
Steps 1 to 3 were performed in a manner similar to what has been described for example 8, step 4 was performed in a manner similar to what has been described for example 11, and steps 5 to 6 were performed in a manner similar to what has been described for example 66.
Step: 7
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-2- methoxymethoxy-ethyl)-2,3-dihydro-lH-indolizin-5-one.
Figure imgf000127_0001
n-Butyl lithium (2.5M solution in hexane) (6.6mL, 6.775mmol) was added dropwise to a stirred solution of tributyl-methoxymethoxymethyl-stannane (3.72g, 10.17mmol) in dry THF at-78°C over a period of 5mins and the resulting mixture was stirred for 5mins. This was followed by addition of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro- 5-oxo-l,2,3, 5-tetrahydro-indolizine-8-carbaldehyde (250mg, 0.678mmol) in THF at - 780C and with continued stirring for a further 40mins at -780C. The reaction mixture was quenched with saturated NH4Cl solution at -780C, warmed to RT and diluted with ethylacetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated. The concentrate was used for next step without further purification.
Step: 8
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(2-methoxymethoxy- acetyl)-2,3-dihydro-lH-indolizin-5-one.
Figure imgf000128_0001
Dess-martin periodinane (0.18Og, 0.0004mol) were added to a stirred solution of 7-(4- bromo-2-fiuoro-phenylamino)-6-fluoro-8-(l-hydroxy-2-methoxymethoxy-ethyl)-2,3- dihydro-lH-indolizin-5-one (0.16Og, 0.0004mol) in DCM (1OmL) and the reaction mixture was stirred for 1.30hrs at RT. This was followed by addition of 1OmL of saturated NaHCOs containing 300mg of sodium thiosulfate.5H2θ and continued stirring for next lOmins. The residual mixture was extracted with ethylacetate and the organic layer was washed with saturated NaHCOs solution, brine, dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel, 60-65% ethylacetate in hexane as eluant) to afford lOOmg (62.8% yield) of 7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-8-(2-methoxymethoxy-acetyl)- 2,3-dihydro-lH-indolizin-5-one as the required product. LCMS purity: 76.1%, m/z = 444 (M+l), 445 (M+2) HPLC: 80%
Step: 9
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(2-hydroxy-acetyl)-2,3- dihydro-lH-indolizin-5-one.
Figure imgf000128_0002
10% aqueous HCl (4mL) and water (3mL) were added to a stirred solution of 7-(4- bromo-2-fluoro-phenylamino)-6-fluoro-8-(2-methoxymethoxy-acetyl)-2,3-dihydro-lH- indolizin-5-one (lOOmg, 0.0002mol) in methanol (3mL) and the resulting mixture was stirred for 18hrs at RT. The reaction mixture was neutralized with saturated NaHCOs solution, diluted with ethylacetate and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by preparative HPLC to afford 14mg (15.7% yield) of 7-(4-bromo-2-fiuoro-phenylamino)-6-fiuoro-8- (2-hydroxy-acetyl)-2,3-dihydro-lH-indolizin-5-one as the required product. LCMS: 98.4%, m/z = 401 (M+2) HPLC: 98.7%
1H NMR (DMSO-D6, 300 MHz): δ 9.0-8.8 (br s, IH), 7.5 (dd, IH), 7.3 (d, IH), 6.9-6.8 (m, IH), 5.2 (t, IH), 4.3-4.0 (m, 2H), 4.0 (t, 2H), 3.3-3.2 (m, 2H), 2.1 (t, 2H)
Scheme: 13
Figure imgf000129_0001
Example: 70
Step: 1
Synthesis of 5-oxo-7-trifluoromethanesulfonyloxy-l,2,3,5-tetrahydro-indolizine-8- carboxyllic acid ethyl ester.
Figure imgf000129_0002
TEA (5.082g, 0.0502242mol) was added to a solution of 7-hydroxy-6-methyl-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (7.Og, 0.03 lmol) dissolved in DCM (7OmL) and the reaction mixture was cooled to -780C. Triflic anhydride (11.5 Ig, 0.041mol) were added to the reaction mixture and the reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was washed with sodium bicarbonate solution (2OmL) and the organic layer was dried and concentrated. The concentrate was purified by column chromatography (using silica gel, 5% MeOH in CHCl3 as eluant) to afford 7.78g (73.0% yield) of 5-oxo-7- trifluoromethanesulfonyloxy-l,2,3,5-tetrahydro-indolizine-8-carboxyllic acid ethyl ester as the required product.
1H NMR (CDCl3, 300 MHz): 6.3 (s, IH), 4.4 (q, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.35 (q, 3H), 1.4 ( t, 3H).
Step: 2
Synthesis of 7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid ethyl ester.
Figure imgf000130_0001
Palladium acetate (0.063g, 0.003mol), BINAP (0.263g, 0.0003mol), cesium carbonate (1.37g, 0.004mol) were dissolved in toluene and the resulting mixture was sparged for 30 mins with nitrogen. This was followed by addition of 5-oxo-7- trifluoromethanesulfonyloxy-l,2,3,5-tetrahydro-indolizine-8-carboxyllic acid ethyl ester ( Ig, 0.003mol) and 2-fluoro-4-trifluoromethyl aniline (0.549g, 0.003mol) and the reaction flask was again sparged for another 15 mins. The reaction mixture was heated at HO0C for 1.30 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrate was purified by column chromatography (using silica gel of mesh size 60-120, 70% MeOH in CHCl3 as eluant) to afford 0.4g (37% yield) of 7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid ethyl ester as the required product.
1H NMR ( DMSO-D6): 7.6 (t, IH), 7.4 (t, 2H), 6.0 (s, IH), 4.4 (q, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.2 (q, 3H), 1.4 (t, 3H)
Example: 71
Steps 1 and 2 were performed in a manner similar to what has been described for example 70. Step: 3
Synthesis of 7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid.
Figure imgf000131_0001
LiOH (0.07g, 0.002mol) was added to a stirred solution of 7-(2-fluoro-4- trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-terahydro-indolizine-8-carboxylic acid ethyl ester (0.3Og, 0.0008mol) dissolved in MeOH:THF (6mL) and the reaction mixture was stirred at RT for 4 hrs. The reaction mixture was concentrated and the concentrate was acidified with 10% HCl to yield a precipitate which was collected and dried to afford 0.27Og (95.74% yield) of 7-(2-fluoro-4-trifluoromethyl-phenylamino)-5- oxo-l,2,3,5-terahydro-indolizine-8-carboxyllic acid as the required product. 1H NMR( DMSO-D6, 300 MHz): 13.4 (s, IH), 10.4 (s, IH), 7.85-7.75 (m, 2H), 7.6 (d, IH), 5.7 (s, IH), 4.0 (t, 2H), 3.5 (t, 2H), 2.1 (t, 2H)
Example: 72.
Steps 1 to 2 were performed in a manner similar to what has been described for example 70 and step 3 was performed in a manner similar to what has been described for example 71.
Step: 4
Syntheis of 7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid cyclopropylmethoxy amide.
Figure imgf000131_0002
EDCI (0.322g, 0.002mol), HOBt (0.23g, 0.002mol) and 7-(2-fluoro-4-trifluoromethyl- phenylamino)-5-oxo-l,2,3,5-terahydro-indolizine-8-carboxyllic acid (0.2g, O.OOlmol) was dissolved in DMF in an inert atmosphere and the reaction mixture was stirred at RT for 30mins. This was followed by addition of cyclopropylmethyl hydroxylamine hydrochloride (0.2 Ig, 0.002mol) and TEA (0.17g, 0.002mol) and the reaction mixture was stirred at RT for 16hrs. Water was added to the reaction mixture and the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate solution, brine solution and dried over Na2SO4 to yield a precipitate which was triturated with ether to afford 0. Ig (41.8% yield) of 7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid cyclopropylmethoxy amide as the pure product. 1H NMR ( DMSO-D6, 300 MHz): 11.4 (s, IH), 8.7 (s, IH), 7.8 (d, IH), 7.65-7.55 (m, 2H), 5.8 (s, IH), 3.8 (t, 2H), 3.6 (d, 2H), 3.2 (t, 2H), 2.2 (t, 2H), 1.25-1.15 (m, IH), 0.65-0.55 (m, 2H), 0.45-0.35 (m, 2H).
Scheme: 14
Figure imgf000132_0001
Example: 73
Step 1 was performed in a manner similar to what has been described for example
70
Step: 2 Synthesis of 7-(2-Fluoro-4-methoxy-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid ethyl ester.
Figure imgf000132_0002
Palladium acetate (0.06g, 0.003mol), BINAP (0.26g, 0.0002mol), cesium carbonate (1.37g, 0.004mol) were dissolved in toluene and the resulting mixture was sparged for 30 mins with nitrogen. This was followed by addition of 5-oxo-7- trifluoromethanesulfonyloxy-l^^^-tetrahydro-indolizine-S-carboxyllic acid ethyl ester ( Ig, 0.003mol) and 2-fluoro-4-methoxy aniline (0.54g, 0.003mol) and the reaction flask was again sparged for another 15 mins. The reaction mixture was heated at HO0C for 1.30 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated. The concentrate was purified by column chromatography (using silica gel, 70% MeOH in CHCl3 as eluant) to afford 0.23Og (23.6% yield) of 7-(2- fluoro-4-methoxy-phenylamino)-5-oxo-l,2,3,5-terahydro-indolizine-8-carboxyllic acid ethyl ester as the required product.
1H NMR (DMSO-D6, 300 MHz): 9.2 (s, IH), 7.2 (t, IH), 6.85-6.75 (m, 2H), 5.5 (s, IH), 4.4 (q, 2H), 4.2 (t, 2H), 3.8 (s, 3H), 3.5 (t, 2H), 2.2 (q, 2H), 1.4 (t, 3H).
Step: 3
Synthesis of 7-(2-Fluoro-4-methoxy-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid.
Figure imgf000133_0001
LiOH (0.05g, 0.00 lmol) was added to a stirred solution of 7-(2-fluoro-4-methoxy- phenylamino)-5-oxo-l,2,3,5-terahydro-indolizine-8-carboxyllic acid ethyl ester (0.19g, 0.00 lmol) dissolved in MeOH:THF (6mL) and the resulting mixture was stirred at RT for 4 hrs. The solvents were distilled and the crude product was acidified with 10% HCl to yield a precipitate which was collected and dried to afford 0. 13Og (76.023% yield) of 7-(2-fluoro-4-methoxy-phenylamino)-5-oxo- 1,2,3, 5-terahydro-indolizine-8- carboxyllic acid.
1H NMR (DMSO-D6, 300 MHz): 13.45-13.35 (br s, IH), 9.6 (s, IH), 7.3 (t, IH), 7.0 (d, IH), 6.8 (d, IH), 5.0 (s, IH), 4.0 (t, 2H), 3.8 (s, 3H), 3.5 (t, 2H), 2.15-2.05 (m, 2H).
Step: 4
Synthesis of 7-(2-Fluoro-4-methoxy-phenylamino)-5-oxo-l,2,3,5-terahydro- indolizine-8-carboxyllic acid cyclopropylmethoxy amide.
Figure imgf000133_0002
EDCI (0.22g, 0.00 lmol), HOBt (0.15g, 0.00 lmol) and 7-(2-fluoro-4-methoxy- phenylamino)-5-oxo-l,2,3,5-terahydro-indolizine-8-carboxyllic acid (0.12g,
0.0004mol) was dissolved in DMF in an inert atmosphere and the reaction mixture was stirred at RT for 30mins. This was followed by addition of cyclopropylmethyl hydroxylamine hydrochloride (0.14Og, 0.00 lmol) and TEA (0.114g, 0.00 lmol) and the reaction mixture was stirred at RT overnight. Water was added to the reaction mixture, followed by saturated NH4Cl and extraction with ethyl acetate. The organic layer was washed with saturated bicarbonate solution, brine solution, dried over Na2SO4 to yield a precipitate, which was triturated with ether to afford 0.09g (61.6% yield) of 7-(2- fluoro-4-methoxy-phenylamino)-5-oxo-l,2,3,5-terahydro-indolizine-8-carboxyllic acid cyclopropylmethoxy amide as the required product.
1H NMR (DMSO-D6, 300 MHz): 11.4 (s, IH), 7.9 (s, IH), 7.2 (t, IH), 6.9 (d, IH), 6.8 (d, IH), 5.0 (s, IH), 3.9 (t, 2H), 3.8 (s, 3H), 3.7 (d, 2H), 3.2 (t, 2H), 2.05-2.0 (m, 2H), 1.05-1.0 (m, IH), 0.65 (d, 2H), 0.2 (d, 2H).
Example: 74 Scheme: 15
Steps 1 to 2 were performed in a manner similar to what has been described for example 27
Step: 3
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid.
Figure imgf000135_0002
LDA (5OmL) were added to a solution of 2-fluoro-4-bromo-phenylamine (7g, 0.037mol) in THF (55OmL) at -780C and the resulting mixture was stirred for lhr. This was followed by addition of 7-chloro-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (5.5g, 0.025mol) in dry THF (20OmL) at -780C and the reaction mass was stirred at room temperature for 16hrs. The reaction mixture was concentrated under reduced pressure, neutralized with dil HCl. Addition of diethyl ether and stirring for lhr yielded a precipitate which was collected to afford 5.2g (56% yield) of 7-(4-bromo-2-fluoro- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid as the required product.
Step: 4
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as- indacene-2,5-dione.
Figure imgf000136_0001
TEA (1.52mg, 0.015mol) were added to a solution of 7-(4-bromo-2-fluoro- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (5g, 0.014mol) in dry DMF (8mL) under nitrogen atmosphere and the reaction mixture was stirred for 30mins. This was followed by dropwise addition of DPPA (4.14g, 0.015mol) over a period of 15mins at 1O0C with stirring. The stirring was continued for a a further 5hrs at RT. This was followed by addition of toluene (8OmL) and the reaction mass was heated to 9O0C for 4hrs. The reaction mass was concentrated under reduced pressure, and was followed by addition of chilled water. The precipitate formed was collected, dried to afford 3.4g (70% yield) of 3-(4-bromo-2-fiuoro-phenyl)-l,6,7,8-tetrahydro-3H-l,3,5a- triaza-as-indacene-2,5-dione as the required product.
Step: 5
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-l-methanesulfonyl-l,6,7,8-tetrahydro-
3H-l,3,5a-triaza-as-indacene-2,5-dione.
Figure imgf000136_0002
60% NaH (70mg, 0.003mol) was added to a stirred solution of 3-(4-bromo-2-fluoro- phenyl)-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (300mg, 0.00 lmol) in dry DMF (1OmL) at 0-50C under nitrogen atmosphere and the resulting mixture was stirred for lhr at RT. This was followed by dropwise addition of methanesulfonyl chloride (150mg, O.OOlmol) in dry THF over a period of 5mins at O0C and with stirring for the next 16hrs at RT. Ice cold water was added into the reaction flask with stirring for 5mins, pH was adjusted to 5. Extraction with ethylacetate, followed by drying over Na2SO4 and concentration under reduced pressure affords 160mg (47% yield) of 3-(4- bromo-2-fluoro-phenyl)- 1 -methanesulfonyl- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a-triaza-as- indacene-2,5-dione as the required product. HPLC: 93.7%
1H NMR (DMSO-D6, 300 MHz): δ, 7.9-7.45 (m, 3H), 5.45 (s, IH), 3.9 (t, 2H), 3.65 (s, 3H), 3.3 (t, 2H), 2.15-2.05 (m, 2H)
Example: 75
Steps 1 to 2 were performed in a manner similar to what has been described for example 27 and steps 3 to 4 were performed in a manner similar to what has been described for example 74.
Step: 5
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-l-cyclopropanesulfonyl-l,6,7,8- tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione.
Figure imgf000137_0001
60% NaH (20mg) was added to a stirred solution of 3-(4-bromo-2-fluoro-phenyl)- l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (200mg, O.OOlmol) in dry DMF (5mL) at 0-50C under nitrogen atmosphere and the resulting mixture was stirred for lhr at RT. This was followed by dropwise addition of cyclopropanesulfonyl chloride (150mg, 0.002mol) in dry THF over a period of lOmins at O0C and the stirring was continued for the next 16hrs at RT. To the reaction mixture were added NaH (20mg) at O0C, stirred for 15mins, followed by addition of cyclopropanesulfonyl chloride (150mg, 0.002mol) in dry DMF and continued stirring for a further 5hrs at RT. The crude product was used for the next step without further purification.
Step: 6 Synthesis of Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000138_0001
IN aqueous NaOH (7mL) was added to 3-(4-bromo-2-fluoro-phenyl)-l- cyclopropanesulfonyl-l^J^-tetrahydro-SH-l^^a-triaza-as-indacene-l^-dione and the resulting mixture was heated to 750C for 4hrs. Ice cold water was added to the reaction mixture, neutralization with 5% ice cold HCl to a pH of about 3 was followed by partitioning between ethylacetate and water. The organic layer was dried over Na2SO4, concentrated, purified by column chromatography (using silica gel , 3% methanol in DCM as eluant) to afford 17mg (7% yield) of cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide as the required product. LC-MS purity: 98.5% HPLC: 97%
1H NMR (DMSO-D6, 300 MHz): δ 8.75 (s, IH), 7.65-7.25 (m, 3H), 5.25 (s, IH), 3.9 (t, 2H), 3.2 (t, 2H), 2.9-2.8 (m, IH), 2.2-2.1 (m, 2H), 0.95-0.85 (m, 4H)
Example: 76
Steps 1 to 2 were performed in a manner similar to what has been described for example 27 and steps 3 to 4 were performed in a manner similar to what has been described for example 74.
Step: 5
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)- 1 -(4-fluoro-benzenesulfonyl)- 1 ,6,7,8- tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione.
Figure imgf000139_0001
60% NaH (50mg, 0.00 lmol) was added to a stirred solution of 3-(4-bromo-2-fluoro- phenyl)-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (300mg, 0.00 lmol) in dry DMF (6mL) at 0-50C under nitrogen atmosphere and the resulting mixture was stirred for lhr at RT. This was followed by dropwise addition of 4-fluoro- benzenesulfonyl chloride (200mg, 0.00 lmol) in dry THF over a period of lOmins and the stirring was continued for the next 16hrs at RT. The crude product was used for the next step without further purification.
Step: 6
Synthesis of N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizin-8-yl]-4-fluoro-benzenesulfonamide.
Figure imgf000139_0002
IN NaOH solution (6mL) was added to 3-(4-bromo-2-fluoro-phenyl)-l-(4-fluoro- benzenesulfonyl)- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a-triaza-as-indacene-2,5-dione and the resulting mixture was heated to 6O0C for lhr. Ice cold water was added to the reaction mixture, neutralization with 5% HCl to a pH of about 4 was followed by partitioning between ethylacetate and water. The organic layer was washed with NaHCO3 , dried over Na2SO4, concentrated, purified by column chromatography (using silica gel, 2% methanol in DCM as eluant) to afford 20mg (6% yield) of N-[7-(4-bromo-2-fluoro- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-4-fluoro-benzenesulfonamide as the required product. LC-MS purity: 97.5% HPLC: 96.274% 1H NMR (DMSO-D6, 300 MHz): δ 9.25 (s, IH), 7.0-7.85 (m, 7H), 5.25 (s, IH), 3.9 (t, 2H), 2.75 (t, 2H), 1.95-1.8 (m,lH)
Example: 77
Steps 1 to 2 were performed in a manner similar to what has been described for example 27 and steps 3 to 4 were performed in a manner similar to what has been described for example 74.
Step: 5
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-2,5-dioxo-2,3,5,6,7,8-hexahydro-l,3,5a- triaza-as-indacene-1-carboxylic acid tert-butyl ester.
Figure imgf000140_0001
60% NaH (67mg, 0.003mol) was added to a stirred solution of 3-(4-bromo-2-fluoro- phenyl)-4-fluoro-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (2.5mg, 0.00 lmol) in dry DMF (1OmL) at O0C under nitrogen atmosphere. This was followed by dropwise addition of BOC anhydride (260mg, 0.00 lmol) in dry THF over a period 5mins of at O0C and the resulting mixture was stirred for 4hr at RT. The crude product was used in the next step without further purification.
Step: 6
Synthesis of [7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizin-8-yl]-carbamic acid tert-butyl ester.
Figure imgf000140_0002
IN aqueous NaOH (6mL) was added to 3-(4-bromo-2-fluoro-phenyl)-2,5-dioxo-
2,3,5,6,7,8-hexahydro-l,3,5a-triaza-as-indacene-l-carboxylic acid tert-butyl ester and the resulting mixture was heated to 650C for 3hrs. Ice cold water was added to the reaction mixture, neutralized with 5% HCl to a pH of about 7 and the reaction mixture was partitioned between ethylacetate and water. The organic layer was dried over Na2SO4, concentrated under reduced pressure and the concentrate was purified by column chromatography (using neutral alumina, 3% methanol in DCM as eluant) to afford 165mg (43.8% yield) of [7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizin-8-yl]-carbamic acid tert-butyl ester as the required product. HPLC: 94.2%
1H NMR (DMSO-D6, 300 MHz): δ 8.15 (s, IH), 7.9-7.45 (m, 3H), 5.15 (s, IH), 3.9 (t, 2H), 2.9 (t, 2H), 2.2-2.1 (m, 2H), 1.45 (s, 9H)
Example: 78
Steps 1 to 2 were performed in a manner similar to what has been described for example 27, steps 3 to 4 were performed in a manner similar to what has been described for example 74, and steps 5 to 6 were performed in a manner similar to what has been described for example 77.
Step: 7
Synthesis of 8-Amino-7-(4-bromo-2-fluoro-phenylamino)-2,3-dihydro-lH- indolizin-5-one.
Figure imgf000141_0001
TFA (ImL) was added dropwise to a stirred solution of [7-(4-bromo-2-fluoro- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-carbamic acid tert-butyl ester (200mg, 0.0005mol) in dry DCM (5mL) over a period of 5mins at -1O0C and the resulting mixture was stirred for 4hrs at RT. The reaction mass was concentrated under reduced pressure. Addition of water, neutralization with NaHCO3 solution and extraction with ethylacetate and drying over Na2SO4 affords 120mg (79% yield) of 8- amino-7-(4-bromo-2-fluoro-phenylamino)-2,3-dihydro-lH-indolizin-5-one as the required product. LCMS purity: 88.3%
Step: 8 Synthesis of Cyclohexanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000142_0001
Pyridine in DCM (4mL) was added to a solution of 8-amino-7-(4-bromo-2-fluoro- phenylamino)-2,3-dihydro-lH-indolizin-5-one (HOmg, 0.0003mol) and the reaction mixture was stirred for lOmins under nitrogen atmosphere. This was followed by addition of DMAP (5mg, 0.0004mol), cooled the reaction mass to 0-50C, added cyclohexyl sulfonyl chloride (80mg, 0.0004mol) in DCM dropwise over a period of lOmins and continued stirring for the next 16hrs at RT. The reaction mixture was partitioned between ethylacetate and water and the organic layer was washed with water and IN dil. HCl. The organic layer was dried over Na2SO4, concentrated and the concentrate was purified by column chromatography (using silica gel , 2% methanol in DCM as eluant) to afford lOmg (8.5% yield) of cyclohexanesulfonic acid [7-(4-bromo- 2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide as the required product.
LC-MS purity: 96.8%, m/z= 484, (M+l) HPLC: 93.4%
1H NMR (DMSO-D6, 300 MHz): δ 7.8 (s, IH), 7.65-7.25 (m, 3H), 5.95 (s, IH), 4.1 (t, 2H), 3.2 (t, 2H), 3.15-3.05 (m, IH), 2.25-2.15 (m, IH), 2.2-2.1 (m, 2H), 1.85-1.75 (m, 2H), 1.65-1.6 (m, 4H), 1.3-1.25 (m, 2H)
Example: 79
Steps 1 to 2 were performed in a manner similar to what has been described for example 27 and steps 3 to 4 were performed in a manner similar to what has been described for example 74.
Step: 5
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-l-(4-trifluoromethyl-benzenesulfonyl)-
1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione.
Figure imgf000143_0001
60% NaH (31mg, O.OOlmol) was added to a stirred solution of 3-(4-bromo-2-fluoro- phenyl)-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (200mg, O.OOlmol) in dry DMF (4mL) at O0C and the resulting mixture was stirred for lhr at RT. This was followed by dropwise addition of 4-trifluoromethyl-benzenesulfonyl chloride (180mg, O.OOlmol) in dry THF over a period of lOmins at O0C .Continued stirring for the next 2 days at RT affords a crude product which was used for the next step without further purification.
Step: 6
Synthesis of N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizin-8-yl]-4-trifluoromethyl-benzenesulfonamide.
Figure imgf000143_0002
IN aqueous NaOH (15mL) was added to 3-(4-bromo-2-fluoro-phenyl)-l-(4- trifluoromethyl-benzenesulfonyl)-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5- dione and the resulting mixture was heated to 650C for 2hrs. The dil. HCl (pH=4) were added to the reaction mass at RT, then the PH was adjusted to 7 using aqueous Na2CO3 and extracted the reaction mass with ethylacetate. The organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure and the concentrate was purified by column chromatography (using silica gel, 1.5% methanol in DCM) to afford 102mg (33% yield) of as the required product. LC-MS purity: 98.9%, m/z= 548, (M+2) HPLC: 99.6% 1H NMR (DMSO-D6, 300 MHz): δ 9.4(s, IH), 7.85-6.85 (m, 7H), 5.25 (s, IH), 3.9 (t, 2H), 2.85 (t, 2H), 2.0-1.9 (m, IH)
Example: 80
Steps 1 to 2 were performed in a manner similar to what has been described for example 27, steps 3 to 4 were performed in a manner similar to what has been described for example 74, steps 5 to 6 were performed in a manner similar to what has been described for example 77, and step 7 was performed in a manner similar to what has been described for example 78.
Step: 8
Synthesis of N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizin-8-yl]-N,N-dimethylaminosulfonamide.
Figure imgf000144_0001
N,N-Dimethyl sulfonyl chloride (40mg, 0.0003mol) was added to a solution of 8- amino-7-(4-bromo-2-fluoro-phenylamino)-2,3-dihydro-lH-indolizin-5-one (80mg, 0.0002mol) in dry THF and DMAP (30mg, 0.0002mol) at -350C and the reaction mixture was stirred at RT for 2hrs. This was followed by addition of dry pyridine (1.5mL) and the reaction mixture was heated to 4O0C for 4hrs. The reaction mass was concentrated under reduced pressure and the concentrate was purified by preparative HPLC to afford 6mg (9% yield) of N-[7-(4-bromo-2-fluoro-phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizin-8-yl]-N,N-dimethylaminosulfonamide as the required product. HPLC: 91.4%
1H NMR (DMSO-D6, 300 MHz): δ 7.15 (s, IH), 7.85-7.25 (m, 3H), 5.9 (s, IH), 4.2 (t, 2H), 3.29 (t, 2H), 2.9 (s, 6H), 2.25-2.15 (m, 2H)
Scheme: 16 Example: 81 ,
Figure imgf000145_0001
Step: 1
Synthesis of 5-Hydroxy-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza- cyclopenta[a]indene-4-carboxylic acid ethyl ester.
Figure imgf000145_0002
Malonyl chloride (8.1Og, 0.057mol) was added dropwise to a solution of (2,2-dimethyl- tetrahydro-[l,3]dioxolo[4,5-c]pyrrol-4-ylidene)-acetic acid ethyl ester (J. Chem. Soc, Perkins Transactions 1 : Organic and Bio-organic Chemistry, pgs 2371-2376, (1987)) (10.2g, 0.048mol) in DCM (30OmL) over a period of 30mins and the reaction mixture was stirred at RT for 3hrs. The reaction mass was quenched with 5mL of TEA and the solvent was concentrated. The concentrate was purified by column chromatography (using silica gel, 30-45% ethylacetate in hexane as eluant) to afford 9.25g (69% yield) of 5-hydroxy-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza- cyclopenta[a]indene-4-carboxylic acid ethyl ester as the required product. 1H NMR (CDCl3, 300 MHz): 11.25-11.15 (br s, IH), 6.0 (s, IH), 6.0-5.95 (m, IH), 5.05-4.95 (m, IH), 4.45-4.35 (m, 3H), 4.15-4.05 (m, IH), 1.45-1.35 (m, 6H), 1.3 (s, 3H).
Step: 2
Synthesis of 2,2-Dimethyl-7-oxo-5-trifluoromethanesulfonyloxy-3a,7,8,8a- tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid ethyl ester.
Figure imgf000146_0001
TEA (4.9g, 0.049mol) was added to a solution of 5-hydroxy-2,2-dimethyl-7-oxo- 3a,7,8,8a-tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid ethyl ester (9.25g, 0.033mol) in DCM (20OmL) at -7O0C. This was followed by dropwise addition of triflic anhydride (12.06g, 0.0427mol) in DCM (50OmL) over a period of lhr and the reaction mixture was stirred at RT for lhr. The reaction mass was partitioned between ethylacetate and water. The organic layer was washed with brine solution and concentrated. The concentrate was purified by column chromatography (using silica gel, as eluant) to afford 9g (64.3% yield) of 2,2-dimethyl-7-oxo-5- trifluoromethanesulfonyloxy-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza- cyclopenta[a]indene-4-carboxylic acid ethyl ester as the required product. 1H NMR (CDCl3, 300 MHz): 6.4 (s, IH), 6.0 (d, IH), 5.0 (t, IH), 4.45-4.35 (m, 3H), 4.15-4.05 (m, IH), 1.45-1.35 (m, 6H), 1.3 (s, 3H).
Step: 3
Synthesis of 5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid ethyl ester.
Figure imgf000146_0002
Palladium acetate (0.47g, 0.002mol), BINAP (1.96g, 0.003mol), cesium carbonate (10.26g, 0.032mol) were dissolved in toluene (20OmL) and the resulting mixture was sparged for 30 mins with nitrogen. This was followed by addition of 2,2-dimethyl-7- oxo-5-trifluoromethanesulfonyloxy-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza- cyclopenta[a]indene-4-carboxylic acid ethyl ester (9g, 0.02 lmol) and 2-fluoro-4-bromo aniline (4.4g, 0.023mol) with continued sparging for a a further 15 mins. The reaction mixture was heated to 900C for 1.30 hrs. The reaction mixture was cooled and diluted with 200 mL of ethylacetate, washed with water, brine solution, dried over Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel, 10-70% ethylacetate in hexane as eluant) to afford 5g (51.5% yield) of 5-(4-bromo- 2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza- cyclopenta[a]indene-4-carboxylic acid ethyl ester as the required product. LCMS: m/z=467 (M+H)
1H NMR (CDCl3, 300 MHz): 9.3 (s, IH), 7.45-7.35 (m, IH), 7.35-7.25 (m, 2H), 6.0 (d, IH), 5.8 (s, IH), 5.0 (t, IH), 4.45-4.35 (m, 2H), 4.15-4.05 (m, IH), 1.45-1.35 (m, 6H), 1.3 (s, 3H).
Step: 4
Synthesis of 5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid.
Figure imgf000147_0001
LiOH (0.22g, 0.005mol) in water was added to a stirred solution of 5-(4-bromo-2- fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza- cyclopenta[a]indene-4-carboxylic acid ethyl ester (Ig, 0.002mol) dissolved in MeOH:THF (1 :4) and the resulting mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated and the residue was partitioned between ethylacetate and water and the aqueous layer was acidified with 10% citric acid solution (pH 2.5).The precipitate formed was collected and dried under reduced pressure to afford the crude product which was purified by preparative HPLC to afford 50mg (58.5% yield) of 5-(4- Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a- aza-cyclopenta[a]indene-4-carboxylic acid as the required product. LCMS purity: 99.5%, m/z=439.0 (M-H) HPLC: 99.3% 1H NMR (DMSO-D6, 300 MHz): 13.65-13.55 (br s, IH), 9.55-9.45 (br s, IH), 7.7 (dd, IH), 7.55-7.45 (m, 2H), 6.0 (d, IH), 5.4 (s, IH), 4.9 (t, IH), 4.05-3.95 (m, 2H), 1.4 (s, 3H), 1.2 (s, 3H).
Example: 82
Steps 1 to 12 were performed in a manner similar to what has been described for example 81.
Step: 5
Synthesis of 5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000148_0001
EDCI (262.4mg, 1.369mmol), HOBt (184.61mg, 1.369mmol) and DIPEA (387mg, 2.736mmol) were added to a stirred solution of 5-(4-bromo-2-fluoro-phenylamino)-2,2- dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4- carboxylic acid (200mg, 0.456mmol) in DMF (5mL) and DCM (5mL). This was followed by addition of O-cyclopropylmethyl-hydroxylamine (168.38mg, 1.369mmol) and the reaction mixture was stirred for 16hrs at RT. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated NaHCOs, brine solution, dried over Na2SO4 and concentrated to afford 120mg (51.7% yield) of 5-(4-bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo- 3a,7,8,8a-tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid cyclopropylmethoxy-amide as the required product. LCMS purity: 82.9 %, m/z=508.1 (M+H). HPLC: 79.5 %
1H NMR (DMSO-D6, 300 MHz): 10.5 (s, IH), 9.3 (s, IH), 7.2-7.4 (m, 3H), 5.9 (s, IH), 5.6 (d, IH), 5.0 (t, IH), 4.45-4.35 (m, IH), 4.15-4.05 (m, IH), 3.95-3.85 (m, IH), 3.85- 3.75 (m, IH), 1.6 (s, 3H), 1.5 (s, 3H), 0.85-0.75 (m, IH), 0.65-0.55 (m, 2H), 0.45-0.35 (m, 2H). Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)- 1 ,2-dihydroxy-5-oxo- 1 ,2,3,5- tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide.
Figure imgf000149_0001
Cone. HCl (3mL) was added to a solution of 5-(4-bromo-2-fluoro-phenylamino)-2,2- dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4- carboxylic acid cyclopropylmethoxy-amide (120mg) dissolved in methanol (3mL) and the resulting mixture was stirred at RT for 3hrs. The reaction mixture was concentrated and the concentrate was triturated twice with ethylacetate (2 x 0.5mL). The dried residue affords 20mg (18.2% yield) of 7-(4-bromo-2-fluoro-phenylamino)-l,2- dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy- amide as the required product. LCMS purity: 95.3 %, m/z=470 (M+H). HPLC: 94.1 %
1H NMR (DMSO-D6, 300 MHz): 11.4 (s, IH), 8.1 (s, IH), 7.6 (dd, IH), 7.45-7.35 (m, 2H), 5.4 (s, IH), 5.1 (d, IH), 4.35-4.25 (m, IH), 3.95-3.85 (m, IH), 3.8-3.7 (m, 3H), 1.25-1.15 (m, IH), 0.6 (d, 2H), 0.4 (d, 2H)
Example: 83
Steps 1 to 12 were performed in a manner similar to what has been described for example 81.
Step: 5
Synthesis of 5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (2-hydroxy- ethoxy)-amide.
Figure imgf000149_0002
EDCI (262.4mg, 1.369mmol), HOBt (186.6mg, 1.369mmol), TEA (279mg, 2.736mmol) and O-(2-tert-butoxy-ethyl)-hydroxylamine (182mg, 1.369mmol) were added to a stirred solution of 5-(4-bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo- 3a,7,8,8a-tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid (200mg, 0.456mmol) in DMF (5mL) and DCM (5mL). The reaction mixture was stirred at RT for 16hrs. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated NaHCOs, brine solution, dried over Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel, 2% methanol in DCM as eluant) to afford lOOmg (39.5% yield) of 5-(4- bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a- aza-cyclopenta[a]indene-4-carboxylic acid (2-hydroxy-ethoxy)-amide as the required product.
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)- 1 ,2-dihydroxy-5-oxo- 1 ,2,3,5- tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
Figure imgf000150_0001
Cone. HCl (3mL) was added to a solution of 5-(4-bromo-2-fluoro-phenylamino)-2,2- dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4- carboxylic acid (2-hydroxy-ethoxy)-amide (lOOmg, 0.18mmol) in methanol (3mL) and the reaction mixture was stirred at RT for 3hrs. The reaction mixture was concentrated and the concentrate was triturated with ethylacetate,The precipitate collected was purified by preparative HPLC to afford 50mg (61.3% yield) of 7-(4-bromo-2-fluoro- phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxy-ethoxy)-amide as the required product. LCMS purity: 98.9 %, m/z=458.0 (M+H). HPLC: 98.7 %
1H NMR (DMSO-D6, 300 MHz): 11.4 (s, IH), 8.2 (s, IH), 7.7 (d, IH), 7.45-7.35 (m, 2H), 5.8 (s, IH), 5.4 (d, IH), 5.3 (s, IH), 5.1 (t, IH), 4.8 (t, IH), 4.3 (t, IH), 4.0 (t, 2H), 3.7-3.9 (m, 2H), 3.65-3.55 (m, 2H). Example: 84
Steps 1 to 12 were performed in a manner similar to what has been described for example 81.
Step: 5
Synthesis of 5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid cyclobutylmethoxy-amide.
Figure imgf000151_0001
EDCI (262.4mg, 1.369mmol), HOBt (61mg, 0.456mmol), TEA (279mg, 2.736mmol) and O-cyclobutylmethyl-hydroxylamine (138mg, 1.369mmol) were added to a stirred solution of 5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid (200mg,
0.456mmol) in DMF (5mL) and DCM (5mL). The reaction mixture was stirred at RT for 16hrs. The reaction mixture was partitioned between water and ethylacetate (2x25mL). The organic layer was washed with saturated NaHCOs, brine solution, dried over Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel, 2% methanol in DCM as eluant) to afford 140mg (61.4% yield) of 5-(4-bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid cyclobutylmethoxy-amide as the required product. LCMS: m/z=522.1 (M+H).
1H NMR (DMSO-D6, 300 MHz): 10.4 (s, IH), 9.2 (s, IH), 7.2-7.4 (m, 3H), 5.8 (s, IH), 5.6 (d, IH), 5.1 (t, IH), 4.4 (d, IH), 3.95-4.05 (m, 3H), 2.85-2.75 (m, IH), 2.15-2.05 (m, 2H), 1.95-1.85 (m, 4H), 1.5 (s, 6H)
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)- 1 ,2-dihydroxy-5-oxo- 1 ,2,3,5- tetrahydro-indolizine-8-carboxylic acid cyclobutylmethoxy-amide.
Figure imgf000152_0001
Cone. HCl (3mL) was added to a solution of 5-(4-bromo-2-fluoro-phenylamino)-2,2- dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4- carboxylic acid cyclobutylmethoxy-amide (130mg, 0.249mmol) dissolved in methanol (3mL) and the resulting mixture was stirred at RT for 3hrs. The reaction mixture was concentrated and the concentrate was triturated with ethylacetate. The precipitate formed was collected, purified by preparative HPLC to afford 35mg (29.1% yield) of 7- (4-bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclobutylmethoxy-amide as the required product. 1H NMR (DMSO-D6, 300 MHz): 11.4 (s, IH), 8.1 (s, IH), 7.7 (d, IH), 7.45-7.35 (m, 2H), 5.3 (s, IH), 5.1 (s, IH), 4.35-4.25 (m, IH), 3.85-3.75 (m, 6H), 3.8-3.7 (m, 3H), 2.65-2.55 (m, IH), 2.05-1.95 (m, 2H), 1.85-1.75 (m, 4H).
Example: 85
Steps 1 to 12 were performed in a manner similar to what has been described for example 81.
Step: 5
Synthesis of 5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a- tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta [a] indene-4-carboxylic acid (3-tert-butoxy-
2-methyl-propoxy)-amide.
Figure imgf000152_0002
EDCI (262.4mg, 1.369mmol), HOBt (186.6mg, 1.369mmol), TEA (279mg,
2.736mmol) and O-(3-tert-butoxy-2-methyl-propyl)-hydroxylamine (220mg, 1.369mmol) were added to a stirred solution of 5-(4-bromo-2-fluoro-phenylamino)-2,2- dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4- carboxylic acid (200mg, 0.456mmol) in DMF (5mL) and DCM (5mL). The reaction mixture was stirred at RT for 16hrs. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated NaHCOs, brine solution, dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by column chromatography (using silica gel , 0-2% methanol in DCM as eluant) to afford lOOmg (37.8% yield) of 5-(4-bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo- 3a,7,8,8a-tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid (3-tert- butoxy-2-methyl-propoxy)-amide as the required product. LCMS purity: 76.9 %, m/z=568.1 (M+H) HPLC: 52.3 %
Step: 6
Synthesis of 7-(4-Bromo-2-fluoro-phenylamino)- 1 ,2-dihydroxy-5-oxo- 1 ,2,3,5- tetrahydro-indolizine-8-carboxylic acid (3-hydroxy-2-methyl-propoxy)-amide.
Figure imgf000153_0001
Cone. HCl (3mL) was added to a solution of 5-(4-bromo-2-fluoro-phenylamino)-2,2- dimethyl-7-oxo-3a,7,8,8a-tetrahydro-l,3-dioxa-7a-aza-cyclopenta[a]indene-4- carboxylic acid (3-tert-butoxy-2-methyl-propoxy)-amide (120mg, 0.21mmol) dissolved in methanol (3mL) and the resulting mixture was stirred at RT for 2hrs. The reaction mixture was concentrated and the concentrate was triturated with ethylacetate to yield a precipitate. Purification by preparative HPLC affords 50mg (48.5% yield) of 7-(4- bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (3-hydroxy-2-methyl-propoxy)-amide as the required product. 1H NMR (DMSO-D6, 300 MHz): 11.4 (s, IH), 8.1 (d, IH), 7.7 (dd, IH), 7.45-7.35 (m, 2H), 5.85-5.75 (m, IH), 5.4 (t, IH), 5.3 (s, IH), 5.15-5.05 (m, IH), 4.7 (dt, IH), 4.35- 4.25 (m, IH), 4.15-4.05 (m, IH), 3.8 (dd, IH), 3.7 (dd, IH), 3.55-3.45 (m, 2H), 1.2 (d, 3H). SCHEME: 17
Steps 1-4 same as example: 8
Figure imgf000154_0001
Example: 86
Steps 1 to 4 were performed in a manner similar to what has been described for example 8.
Step: 5
Synthesis of 4-Fluoro-3-(2-fluoro-4-iodo-phenyl)-l,6,7,8-tetrahydro-3H-l,3,5a- triaza-as-indacene-2,5-dione
Figure imgf000154_0002
TEA (1.3OmL, 9.259mmol) and DPPA (2.OmL, 9.259mmol) were added to a stirred solution of 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (4.Og, 9.259mmol) in DMF (3OmL) at O0C and the reaction mixture was stirred for 4hrs at RT under nitrogen atmosphere. The reaction mixture was heated to 650C overnight. The reaction was monitored by TLC (15% MeOH in DCM). The resulting reaction mixture was cooled, addition of water fecilitated the formation of a precipitate which was collected and dried under reduced pressure to afford 3.65g of the product (91% yield). LCMS purity: 98.96%, m/z = 429.9 (M+l)
HPLC: 84.6%
1H NMR (DMSO-D6, 300 MHz): δ 11.3 (s, IH), 7.9-7.25 (m, 3H), 4.0 (t, 2H), 3.1 (t,
2H), 2.3-2.2 (m, 2H)
Step: 6
Synthesis of l-(l-Allyl-cyclopropanesulfonyl)-4-fluoro-3-(2-fluoro-4-iodo-phenyl)-
1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione
Figure imgf000155_0001
60% NaH (0.37g, 9.324mol) was added to a stirred solution of 4-fluoro-3-(2-fluoro-4- iodo-phenyl)-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (2.Og,
4.662mmol) in dry DMF (2OmL) at O0C, under nitrogen atmosphere and the resulting mixture was stirred for 20mins at O0C. This was followed by the addition of 1-allyl- cyclopropanesulfonyl chloride (1.26g, 6.993mol) at O0C and stirring was continued for the next 18hrs at RT. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with water, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 1.22g of the product (46% yield).
LCMS purity: 77.1%, m/z = 573.9 (M+l)
1H NMR (CDCl3, 300 MHz): δ 7.62 (d, 2H), 7.15 (t, IH), 5.7-5.6 (m, IH), 5.1 (d, 2H), 4.4 (t, 2H), 3.5 (t, 2H), 2.7-2.6 (m, 2H), 2.3-2.2 (m, 2H), 1.9-1.8 (m, IH), 1.8-1.7 (m, IH), 1.2-1.1 (m, 2H)
Step: 7
Synthesis of l-Allyl-cyclopropanesulfonic acid [6-fluoro-7-(2-fluoro-4-iodo- phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide
Figure imgf000156_0001
Potassium trimethyl silanoate (0.23g, 1.776mmol) was added to a solution of l-(l-allyl- cyclopropanesulfonyl)-4-fluoro-3-(2-fluoro-4-iodo-phenyl)- 1,6,7, 8-tetrahydro-3H- l,3,5a-triaza-as-indacene-2,5-dione (0.5Og, 0.888mmol) in THF (1OmL). The reaction mixture was refluxed at 650C for 30mins. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated. The concentrate was washed with ether to afford 405mg of the product (83% yield). LCMS purity: 92.%, m/z = 548 (M+ 1) HPLC: 95.8%
1H NMR (CDCl3, 300 MHz): δ 7.4-7.3 (m, 2H), 6.7 (s, IH), 6.6-6.5 (m, IH), 5.8-56 (m, IH), 5.2-5.1 (m, 2H), 4.2 (t, 2H), 3.3 (t, 2H), 2.7 (d, 2H), 2.3-2.1 (m, 2H), 1.3 (t, 2H), 0.8 (t, 2H)
Step: 8
Synthesis of l-(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [6-fluoro-7-(2- fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000156_0002
N-Methyl-morpholine-N-oxide (0.078g, 0.676mmol) and OsO4 (0.02g, 0.067mmol) were added to a stirred solution of 1-allyl-cyclopropanesulfonic acid [6-fluoro-7-(2- fluoro-4-iodo-phenylamino)-5-oxo- 1 ,2,3,5-tetrahydro-indolizin-8-yl]-amide (0.37g, 0.676mmol) in THF (1OmL) and the resulting mixture was stirred at RT overnight. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (5% methanol in chloroform) afforded 86mg of the product (22% yield).
LCMS purity: 96.2%, m/z = 582.1 (M+l)
HPLC: 98.7%
1H NMR (DMSO-D6, 300 MHz): δ 8.95-8.85 (br s, IH), 7.9-7.8 (br s, IH), 7.6 (d, IH),
7.45 (d, IH), 6.9-6.7 (m, IH), 4.8-4.6 (m, 2H), 4.2-4.0 (m, 2H), 3.8-3.7 (m, IH), 3.4-3.2
(m, 3H), 2.3 (d, IH), 2.1 (t, 2H), 1.6-1.4 (m, IH), 1.1-0.8 (m, 3H)
Example: 87
Steps 1 to 3 were performed in a manner similar to what has been described for example 14, and step 4 was performed in a manner similar to what has been described for example 15.
Step-5
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-4-methyl- 1 ,6,7,8- tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione.
Figure imgf000157_0001
Using the same reaction conditions as in step 5 of Example 86, 7-(4-bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (2.75g, 7.21784mmol) in DMF (2OmL) was reacted with TEA (1.OmL, 7.218mmol) and DPPA (1.55mL, 7.218mmol) to afford 2.2g of the product (80% yield).
1H NMR (DMSO-D6, 300 MHz): δ 11.0 (s, IH), 7.8 (dd, IH), 7.6 (m, 2H), 4.0 (t, 2H), 3.0 (t, 2H), 2.2 (t, 2H), 1.5 (s, 3H)
Step-6
Synthesis of l-(l-Allyl-cyclopropanesulfonyl)-3-(4-bromo-2-fluoro-phenyl)-4- methyl- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione.
Figure imgf000158_0001
TEA (0.15mL, l.Oβmmol) was added to stirred solution of 3-(4-bromo-2-fluoro- phenyl)-4-methyl-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (0.2Og, 0.531mmol) in DCM (8mL) at O0C. This was followed by the addition of 1-Allyl- cyclopropanesulfonyl chloride (0.196g, l.Oβmmol) and DMAP (0.013g, O.lOβmmol) at O0C and the resulting mixture was stirred at RT overnight. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was partitioned between water and DCM. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 70mg of the product (25% yield). 1H NMR (DMSO-D6, 300 MHz): δ 7.5-7.3 (m, 3H), 5.9-5.6 (m, IH), 5.1-4.9 (m, 3H), 4.2 (t, 2H), 3.5 (t, 2H), 2.7 (t, 2H), 2.3-2.1 (m, 2H), 2.1-2.0 (m, 2H), 1.9-1.8 (m, IH), 1.8-1.7 (m, 2H), 1.2-1.1 (m, 4H)
Step-7
Synthesis of l-Allyl-cyclopropanesulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide
Figure imgf000158_0002
Using the same reaction conditions as in step 7 of Example 86, l-(l-allyl- cyclopropanesulfonyl)-3-(4-bromo-2-fluoro-phenyl)-4-methyl- 1,6,7, 8-tetrahydro-3H- l,3,5a-triaza-as-indacene-2,5-dione (0.065g, 0.124mmol) in THF (4.OmL) was reacted with potassium trimethyl silanoate (0.032g, 0.249mmol) to afford 40mg of the product (59% yield). LCMS purity: 87.3%, m/z = 497.9 (M+) 1H NMR (DMSO-D6, 300 MHz): δ 8.9-8.8 (br s, IH), 7.5 (d, IH), 7.35 (s, IH), 7.2 (d, IH), 6.4 (t, IH), 5.7-5.5 (m, IH), 5.1-4.9 (m, 2H), 4.1 (t, 2H), 3.2 (t, 2H), 2.6 (d, 2H), 2.2-2.1 (m, 2H), 1.7 (s, 3H), 1.05 (t, 2H), 0.75 (t, 2H)
Step-8
Synthesis of l-(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(4-bromo-2- fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000159_0001
Using the same reaction conditions as in step 8 of Example 86, 1-Allyl- cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- l,2,3,5-tetrahydro-indolizin-8-yl]-amide (0.025g, 0.050mmol) in THF (4.OmL) was reacted with N-methyl-morpholine-N-oxide (0.006g, 0.050mmol), OsO4 (0.00 Ig, 0.005mmol) to afford the crude product. Purification by column chromatography on silica gel (5% methanol in DCM), followed by preparative HPLC afforded 8mg of the product (26% yield). LCMS purity: 96.32%, m/z = 530 (M+) HPLC: 93.5%
1H NMR (CDCl3-D6, 300 MHz): δ 7.45-7.4 (br s, IH), 7.21 (d, IH), 7.15 (d, IH), 7.1- 7.0 (br s, IH), 6.45 (t, IH), 4.25 (t, 2H), 4.1-3.9 (m, IH), 3.7-3.6 (m, IH), 3.5-3.4 (m, IH), 3.3 (t, 2H), 2.4-2.1 (m, 3H), 1.8-1.6 (m, 4H), 1.6-1.3 (m, 2H), 0.9 (t, 2H)
Example: 88
Steps 1 to 3 were performed in a manner similar to what has been described for example 8, step 4 was performed in a manner similar to what has been described for example 11 and step 5 was performed in a manner similar to what has been described for example 61.
Step-6 Synthesis of l-(l-Allyl-cyclopropanesulfonyl)-3-(4-bromo-2-fluoro-phenyl)-4- fluoro- 1 ,6,7,8- tetrahydro-3H- 1 ,3,5a-triaza-as-indacene-2,5-dione
Figure imgf000160_0001
Using the same reaction conditions as in step 6 of Example 86, 3-(4-bromo-2-fluoro- phenyl)-4-fluoro-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5-dione (1-Og,
2.624mmol) in DMF (12mL) was reacted with NaH (0.21g, 5.249mmol) and 1-allyl- cyclopropanesulfonyl chloride (0.71g, 3.937mmol) to afford the crude product. Purification by column chromatography on silica gel (5% methanol in DCM) afforded 300mg of the product (21% yield). LCMS purity: 97.3%, m/z = 526 (M+) HPLC: 95.2%
1H NMR (CDCl3, 300 MHz): δ 7.5-7.4 (m, 2H), 7.35 (d, IH), 5.8-5.6 (m, IH), 5.1 (d, 2H), 4.25 (t, 2H), 3.45 (t, 2H), 2.8-2.6 (m, 2H), 2.3-2.1 (m, 2H), 2.0-1.7 (m, 2H), 1.3- 1.1 (m, 2H)
Step-7
Synthesis of l-Allyl-cyclopropanesulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide
Figure imgf000160_0002
Using the same reaction conditions as in step 7 of Example 86, l-(l-allyl- cyclopropanesulfonyl)-3-(4-bromo-2-fluoro-phenyl)-4-fluoro-l,6,7,8-tetrahydro-3H- l,3,5a-triaza-as-indacene-2,5-dione (0.26g, 0.494mmol) in THF (8mL) was reacted with potassium trimethyl silanoate (0.12g, 0.989mmol) to afford 195mg of the product (79.2% yield).
LCMS purity: 96.4%, m/z = 500.0 (M+) HPLC: 98.5% 1H NMR (CDCl3, 300 MHz): δ 7.25-7.1 (m, 2H), 6.8-6.1 (m, IH), 6.65 (s, IH), 6.4 (s, IH), 5.8-5.6 (m, IH), 5.2-5.1 (m, 2H), 4.2 (t, 2H), 3.3 (t, 2H), 2.7 (d, 2H), 2.3-2.1 (quin, 2H), 1.3 (t, 2H), 0.85 (t, 2H)
Step-8
Synthesis of l-(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(4-bromo-2- fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000161_0001
Using the same reaction conditions as in step 8 of Example 86, 1-allyl- cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5- tetrahydro-indolizin-8-yl]-amide (0.19g, 0.38mmol) in THF (4.OmL) was reacted with N-methyl-morpholine-N-oxide (0.045g, 0.380mmol), OsO4 (O.Olg, 0.038mmol) to afford the crude product. Purification by column chromatography on silica gel (7% methanol in chloroform) afforded 68mg of the product (34% yield). LCMS purity: 96.8%, m/z = 534.0 (M+) HPLC: 99.7%
1H NMR (DMSO-D6, 300 MHz): δ 8.95-8.85 (br s, IH), 7.9-7.8 (br s, IH), 7.55 (d, IH), 7.3 (d, IH), 7.1-6.9 (m, IH), 4.8-4.6 (m, 2H), 4.1 (t, 2H), 3.8-3.7 (br s, IH), 3.3- 3.1 (m, 4H), 2.3 (d, IH), 2.1 (m, 2H), 1.6-1.5 (m, IH), 1.2-0.8 (m, 4H)
Example: 89
Steps 1 to 4 were performed in a manner similar to what has been described for example 8
Step-5
Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-amide
Figure imgf000162_0001
EDCI (1.45mg, 0.008mol) and HOBt (1.03g, 0.008mol) were added to a solution of 6- fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8- carboxylic acid (l.lg, 0.003mol) in DMF (2OmL). The reaction mixture was stirred at RT for lhr. This was followed by the addition of O-(2,2-dimethyl-[l,3]dioxolan-4- ylmethyl)-hydroxylamine (1.12g, 0.008mol) and TEA (0.77g, 0.008mol). The resulting mixture was stirred at RT for 18hrs. The reaction mixture was partitioned between ethyl acetate (10OmL) and water (15OmL). The organic layer was washed with saturated NaHCOs solution (5OmL), NH4Cl, brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 780mg of the crude compound which was used in the next step without further purification.
Step-6
Synthesis of Synthesis of 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5- tetrahydro-indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide.
Figure imgf000162_0002
2N HCl (5 ml) was added to a solution of 6-fluoro-7-(2-fluoro-4-iodo-phenylamino)-5- oxo-1, 2, 3, 5-tetrahydro-indolizine-8-carboxylic acid (2, 3-dihydroxy-propoxy)-amide (780mg, 0.00 lmol) in methanol (20ml). The reaction mixture was stirred at RT for lhr. The reaction mixture was concentrated under reduced pressure, followed by the addition of IN NaOH till the pH is about 8 and extracted with ethyl acetate (2XlOOmI). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 250mg of the crude product. Purification by preparative HPLC afforded 18 mg of the product (2.4% yield). LC-MS purity: 96%, m/z = 521.9, (M+) 1H NMR (DMSO-D6, 300 MHz): δ 11.5 (s, IH), 8.06 (s, IH), 7.58 (d,lH), 7.42 (d, IH), 6.80 (t, IH), 4.9-4.4 (m, 2H), 4.00 (t, 2H), 3.9-3.8 (m, IH), 3.7-3.6 (m, 3H), 3.14-3.12 (m, 3H) 2.18-2.04 (m, 2H)
Example: 90 SCHEME: 18
Figure imgf000163_0001
Step 1 was performed in a manner similar to what has been described for example
18
Step-2
Synthesis of 7-Chloro-6-methyl-5-oxo-l, 2, 3, S-tetrahydro-indolizine-δ-carboxylic acid ethyl ester
Figure imgf000163_0002
Phosphorusoxy chloride (5.8g, 0.038mol) was added to a solution of 7-hydroxy-6- methyl-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (2g, 0.008mol) in toluene (75mL) at RT. The reaction mixture was stirred for 2 hrs at HO0C. The reaction was monitored by TLC (60% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure, followed by the addition of ice water (5OmL) and saturated K2CO3 solution (75mL) (pH=10). The resulting reaction mixture was extracted with ethyl acetate (3X5 OmL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 1.6g of crude compound. Purification by recrystallization using hexane afforded 1.54g of the product (% yield).
Step-3
Synthesis of 7-Chlor<)-6-methyl-5-oxo-l, 2, 3, S-tetrahydro-indolizine-δ-carboxylic acid
Figure imgf000164_0001
IN LiOH solution (25mL) was added to a solution of 7-chloro-6-methyl-5-oxo-l, 2, 3,
S-tetrahydro-indolizine-S-carboxylic acid ethyl ester (1.5g, O.OOβmol) in 75ml of THF:
MeOH (4:1). The reaction mixture was stirred at RT for 18 hours. The reaction was monitored by TLC (20% methanol in DCM). The reaction mixture was concentrated under reduced pressure, followed by the addition of IN HCl (10OmL) till the pH is about 1. The precipitate was collected and dried under reduced pressure to afford 1.12g of the product (84% yield).
LC-MS purity: 98%, m/z = 226 (M-)
1H NMR (DMSO- D6, 300 MHz): δ 13.2 (s, IH), 4.00 (t, 2H), 3.28 (t, 2H), 2.2-2.02
(m, 5H)
Step-4
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5- tetrahydro-indolizine-8-carboxylic acid
Figure imgf000164_0002
LDA (1.86g, 0.017mol) was added to a solution of 2-fluoro-4-iodo-phenylamine (2.9g, 0.012mol) in dry THF (2OmL) at -780C. The reaction mixture was stirred for 45 minutes at -780C. This was followed by addition of 7-Chloro-6-methyl-5-oxo-l, 2, 3, 5- tetrahydro-indolizine-S-carboxylic acid (l.lg, 0.005mol) in THF (9OmL) at -780C and stirring was continued for a further 20 hrs at RT. The reaction was monitored by TLC
(20% methanol in DCM). The reaction mixture was concentrated under reduced pressure, followed by the addition of 2N HCl solution (5OmL) and diethyl ether
(5OmL). The reaction mixture was stirred for 15 minutes. The precipitate was collected, washed with diethyl ether (2X20mL) and dried under reduced pressure to afford 820mg of the product (41% yield).
LC-MS purity: 94%, m/z = 429 (M+)
1H NMR (DMSO-D6, 300 MHz): δ 13.30 (s, IH), 9.36 (s, IH), 7.60 (d, IH), 7.38 (s,
IH), 6.40 (t, IH), 4.04 (t, 2H), 3.48 (t, 2H), 2.18-2.02 (m, 2H), 1.64 (s, 3H)
Step-5
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5- tetrahydro-indolizine-8-carboxylic acid cyclopropyl methoxy amide.
Figure imgf000165_0001
EDCI (334mg, 0.002mol) and HOBt (236mg, 0.002mol) were added to a solution of 7- (2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8- carboxylic acid (250mg, O.OOlmol) in DMF (1OmL). The reaction mixture was stirred at RT for lhr. This was followed by the addition of O-cyclopropylmethyl- hydroxylamine hydrochloride (216mg, 0.002mol) and TEA (176mg, 0.002mol). The resulting mixture was stirred at RT for 2hrs. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was partitioned between ethyl acetate (75mL) and water (125mL). The organic layer was washed with saturated NH4Cl (5OmL), NaHCθ3, brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 210 mg of the crude compound. Purification by recrystallization using methanol (2mL) and diethyl ether (2OmL) afforded 140 mg of the product (48.2% yield). LC-MS purity: 97%, m/z = 498, (M+)
1H NMR (DMSO-D6, 300 MHz): δ 11.22 (s, IH), 7.7 (s, IH), 7.56 (d,lH), 7.32 (d, IH), 6.40 (t, IH), 4.02 (t, 2H), 3.48 (d, 2H), 3.2 (t, 2H), 2.18-2.04 (m, 2H), 1.68 (s, 3H), 1.04-.094 (m, IH), 0.58-0.46 (m, 2H), 0.26-0.18 (m, 2H). Example: 91
Step 1 was performed in a manner similar to what has been described for example 14, and step 2 to 4 were performed in a manner similar to what has been described for example 90.
Step-5
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5- tetrahydro-indolizine-8-carboxylic acid (2-tert-butoxy-ethoxy)-amide
Figure imgf000166_0001
EDCI (334mg, 0.002mol) and HOBt (236mg, 0.002mol) were added to a solution of 7- (2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8- carboxylic acid (250mg, 0.001 mo 1) in DMF (1OmL). The reaction mixture was stirred at RT for 30 minutes. This was followed by the addition of O-(2-tert-butoxy-ethyl)- hydroxylamine (233 mg, 0.002mol) and TEA (176mg, 0.002mol). The resulting mixture was stirred at RT for 16hrs. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was partitioned between ethyl acetate (10OmL) and water (10OmL). The organic layer was washed with saturated NH4Cl (5OmL), NaHCOs, brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 300 mg of the crude compound. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 228 mg of the product (71% yield). LC-MS purity: 96%, m/z = 544, (M+)
Step-6
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2,3, 5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
Figure imgf000167_0001
Trifluoro acetic acid (2.5mL) was added to a solution of 7-(2-fluoro-4-iodo- phenylamino)-6-methyl-5-oxo-l, 2, 3, S-tetrahydro-indolizine-S-carboxylic acid (2-tert- butoxy-ethoxy)-amide (220mg, 0.0004mol) in DCM (2.5mL) at O0C. The reaction mixture was stirred for 2 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was concentrated under reduced pressure, followed by the addition of NaHCOs till the pH is about 8 and extracted with ethyl acetate. The combined organic layers were washed with 5% NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. The concentrate was washed with diethyl ether and ethyl acetate to afford 89mg of the product (45% yield). LC-MS purity: 93%, m/z = 488, (M+)
1H NMR (DMSO-D6, 300 MHz): δ 11.24 (s, IH), 7.68 (s, IH), 7.54 (d,lH), 7.32 ( d, IH), 6.40 (t, IH), 4.7 (s, IH), 4.00 (t, 2H), 3.7 (t, 2H), 3.55-3.42 (m, 2H), 3.18 (t, 2H), 2.18-2.04 (m, 2H), 1.72 (s, 3H)
Example: 92
Step 1 was performed in a manner similar to what has been described for example 14 and step 2 to 4 were performed in a manner similar to what has been described for example 90.
Step-5
Synthesis of 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclobutylmethoxy-amide.
Figure imgf000167_0002
EDCI (167mg, O.OOlmol) and HOBt (118mg, O.OOlmol) were added to a solution of 7- (2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8- carboxylic acid (125mg, 0.0003mol) in DMF (8mL). The reaction mixture was stirred at RT for lhr. This was followed by the addition of O-cyclobutylmethyl-hydroxylamine (88mg, 0.001 mo 1) and TEA (88mg, O.OOlmol). The resulting mixture was stirred at RT for 2hrs. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was partitioned between ethyl acetate (5OmL) and water (75mL). The organic layer was washed with saturated NH4Cl (5OmL), NaHCOs, brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 150 mg of the crude compound. Purification by recrystallization using ethyl acetate (1OmL) and diethyl ether (5OmL) afforded 85mg of the product (57% yield). LC-MS purity: 94%, m/z = 512, (M+)
1H NMR (DMSO-D6, 300 MHz): δ 11.2 (s, IH), 7.68 (s, IH), 7.58 (d,lH), 7.34 (d, IH), 6.40 (t, IH), 4.00 (t, 2H), 3.56 (d, 2H), 3.18 (t, 2H), 2.18-2.04 (m, 2H), 2.02-1.92 (m, 3H), 1.9-1.62 (m, 7H).
Example: 93
Steps and 3 were performed in a manner similar to what has been described for example 14, and step 4 was performed in a manner similar to what has been described for example 15.
Step-5
Synthesis of 3-(2-Fluoro-4-iodo-phenyl)-4-methyl- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione
Figure imgf000168_0001
Using the same reaction conditions as in step 5 of Example 86, 7-(2-fluoro-4-iodo- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizine-8-carboxylic acid (3.14g,
7.34mmol) in DMF (3OmL) was reacted with TEA (1.03mL, 7.34mmol) and DPPA
(1.59mL, 7.34mmol) to afford 1.85g of the product (59% yield).
LCMS purity: 97.0%, m/z = 426.0 (M+)
1H NMR (DMSO-D6, 300 MHz): δ 11.1 (s, IH), 7.9 (d, IH), 7.7 (d, IH), 7.4-7.1 (m,
2H), 3.9 (t, 2H), 3.1 (t, 2H), 2.4-2.2 (m, 2H), 1.45 (s, 3H)
Step-6 Synthesis of l-(l-Allyl-cyclopropanesulfonyl)-3-(2-fluoro-4-iodo-phenyl)-4-methyl- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione.
Figure imgf000169_0001
Using the same reaction conditions as in step 6 of Example 109 (current set), 3-(2- fluoro-4-iodo-phenyl)-4-methyl-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5- dione (1.8Og, 4.24mmol) in DMF (2OmL) was reacted with NaH (0.34g, 8.47mmol) and 1-allyl-cyclopropanesulfonyl chloride (1.14g, 6.35mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 490mg of the product (20% yield). LCMS purity: 83.9%, m/z = 569.9 (M+)
1H NMR (CDCl3, 300 MHz): δ 7.7-7.6 (m, 2H), 7.15 (t, IH), 5.7-5.6 (m, IH), 5.1-4.9 (m, 2H), 4.2 (t, 2H), 3.5 (t, 2H), 2.7 (t, 2H), 2.3-2.1 (m, 3H), 1.9-1.8 (m, IH), 1.8-1.6 (m, IH), 1.3-1.11 (m, 2H)
Step-7
Synthesis of l-Allyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-
6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide
Figure imgf000169_0002
Using the same reaction conditions as in step 7 of Example 109 (current set), 1-(1-
Allyl-cyclopropanesulfonyl)-3-(2-fluoro-4-iodo-phenyl)-4-methyl- 1,6,7, 8-tetrahydro-
3H-l,3,5a-triaza-as-indacene-2,5-dione (0.48g, 0.84mmol) in THF (12mL) was reacted with potassium trimethyl silanoate (0.2 Ig, 1.69mmol) to afford 310mg of the product
(63% yield).
LCMS purity: 85.2%, m/z = 544.0 (M+)
HPLC: 86.7% 1H NMR (DMSO-D6, 300 MHz): δ 8.8 (s, IH), 7.6 (d, IH), 7.35 (d, 2H), 6.3 (t, IH), 5.7-5.5 (m, IH), 5.1 (d, 2H), 4.1 (t, 2H), 3.25 (t, 2H), 2.6 (d, 2H), 2.1 (quin, 2H), 1.7 (s, 3H), 1.1 (t, 2H), 0.75 (t, 2H)
Step-8
Synthesis of l-(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(2-fluoro-4- iodo-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000170_0001
Using the same reaction conditions as in step 8 of Example 109 (current set), 1-allyl- cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2,3,5- tetrahydro-indolizin-8-yl]-amide (0.25g, 0.46mmol) in THF (1OmL) was reacted with N-methyl-morpholine-N-oxide (0.054g, 0.46mmol), OsO4 (O.Olg, 0.046mmol) to afford the crude product. Purification by column chromatography on silica gel (5% methanol in CHCI3), followed by preparative HPLC afforded 95mg of the product (36% yield).
LCMS purity: 96.7%, m/z = 577.8 (M+) HPLC: 97.2%
1H NMR (DMSO-D6, 300 MHz): δ 8.75 (s, IH), 7.6-7.3 (m, 3H), 6.3 (t, IH), 4.6 (t, 2H), 4.1 (t, 2H), 3.6-3.5 (m, IH), 3.3-3.2 (m, 4H), 2.1-2.0 (m, 3H), 1.75-1.6 (m, 5H), 1.3-1.0 (m, 4H)
SCHEME: 19
Figure imgf000170_0002
Example: 94
Steps 1 to 3 were performed in a manner similar to what has been described for example 14, step 4 was performed in a manner similar to what has been described for example 15, and step 5 was performed in a manner similar to what has been described for example 87.
Step-6
Synthesis of 3-(4-Bromo-2-fluoro-phenyl)-l-cyclopropanesulfonyl-4-methyl-
1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione.
Figure imgf000171_0001
Sodium hydride (0.04gm, 0.00 lmol) was added to a solution of 3-(4-bromo-2-fluoro- phenyl)-4-methyl- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a-triaza-as-indacene-2,5-dione (0.2 gm, 0.0005mol) in dry DMF (3ml) at O0C. This was followed by the addition of cycolpropanesulfonyl chloride (0.1 lgm, 0.0008mol) at O0C and the reaction mixture was stirred at RT overnight. The reaction was monitored by TLC (5% MeOH in CHCI3). Addtion of ice, neutralization with dil.HCl , extraction with ethyl acetate followed by concentration afforded 0.25g of the crude product which was used in the next step without further purification.
Step-7
Synthesis of Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6- methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide.
Figure imgf000171_0002
6ml of IN NaOH solution was added to 3-(4-bromo-2-fluoro-phenyl)-l- cyclopropanesulfonyl-4-methyl-l,6,7,8-tetrahydro-3H-l,3,5a-triaza-as-indacene-2,5- dione (0.25g) in DMF and heated the mixture to 650C for 1.30hrs. Addtion of ice, neutralization with dil.HCl , extraction with ethyl acetate followed by concentration and purification by column chromatography on silica gel (2% methanol in CHCI3) afforded 0.09Og of the product (37.34% yield). 1H NMR (DMSO-D6, 300 MHz): δ 8.9 (s, IH), 7.5 (d, IH), 7.4 (s, IH), 7.2 (d, IH), 6.5 (t, IH), 4.0 (t, 2H), 3.3 (t, 2H), 2.5 (m, IH), 2.1 (q, 2H), 1.7 (s, 3H), 0.9 (m, 4H)
The compounds of the above Examples were evaluated as inhibitors of the MAP kinase pathway in a BRAF-MEK-ERK enzymatic cascade assay and in a cell viability assay, the results of which are collated in Table 1. It is recognized that Other compounds described herein can be made by a person of ordinary skill in the art using methods known to him and/or described herein.
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
The examples provided in the description are only to describe the invention, hence it should not be construed to limit the scope of the invention.

Claims

WE CLAIM:
1. A compound of formula I:
Figure imgf000187_0001
and pharmaceutically acceptable salts thereof, wherein
X represents Ci-3-alkylene, -N(R6)-, -O-, or -S(O)P-;
R1 represents aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein said rings are optionally substituted by one or more groups independently selected from List 1;
R2 represents H, cyano, or the group -Y-R7;
R3 and R4 independently represent H, Ci_6-alkyl, Ci_6-haloalkyl, Ci_6-hydroxyalkyl, hydroxyl, Ci_6.alkoxy, amino, Ci_6-alkylamino, diCi_6-alkylamino, or R3 additionally represents monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings are optionally substituted by one or more groups independently selected from List 1;
R5 represents H, halogen, Ci_3_alkyl, or Ci_3_haloalkyl;
Y represents a group selected from -D-, -E-, -D-E-, or -E-D-;
D represents a group selected from -N(R8)-, -CO-,-CO2-, -SO-, -SO2-, C0N(R9)0-, - CON(R10)-, -N(R1 ^SO2-, -N(R24)SO2NR25-, -SO2N(R12)-, -N(R13)C0-, - N(R14)CON(R15)-, -N(R16)C0-, or -C(=NH)N(R17)-;
E represents a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said rings are optionally substituted by one or more groups independently selected from List 1; R7 represents H, Ci-6-alkyl, C2-6-alkenyl C2-6-alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein R7 when not H is optionally substituted by one to three groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy, C2- C6-alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci-βhaloalkyl, amino, Ci_6alkylamino, di- Ci_6alkylamino, Ci_6acylamino, Ci_6acylCi_6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings may be optionally substituted by one or two groups independently selected from halogen, cyano, hydroxyl, Ci_6.alkoxy, C2-C6- alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci_6-haloalkyl, amino, Ci_6-alkylamino, di- Ci_6-alkylamino, Ci_6-acylamino and C i_6-acylCi_6- alkylamino;
Z is O or N(R18);
List 1 is selected from hydroxyl, cyano, nitro, Ci-6-alkyl, C2-6.alkenyl, C2-6.alkynyl, Cp6- alkoxy, C2-6_alkenyloxy, C2-6_alkynyloxy, halogen, Cp6_alkylcarbonyl, carboxy, Cp6. alkoxycarbonyl, amino, Ci-6.alkylamino, di-Ci-6.alkylamino, Ci-6-alkylaminocarbonyl, di-Cp6. alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6.alkyl)amino, Cp6. alkylsulfonylamino, Ci-6-alkylsulfonyl(Ci-6-alkyl)amino, Ci-6.thioalkyl, Ci-6-alkylsulfinyl, Cp6. alkylsulfanyl, Cp6_alkylsulfonyl, aminosulfonyl, Cp6.alkylaminosulfonyl and di-Cp6. alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Cp6.alkoxy, amino, Cp6-alkylamino, di-Cp6. alkylamino or cyano;
R26 represents H, Ci_6-alkyl, Ci_6-haloalkyl, Ci_6-hydroxyalkyl, hydroxyl, Ci_6-alkoxy, amino, Ci_6-alkylamino, or diCi_6-alkylamino;
R6, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 R18, R24, and R25 are independently H or Ci_6-alkyl;
m and n are independently 0, 1, 2, or 3; and m + n = 2 or 3;
p is 0, 1, or 2; and wherein
Alkyl or alkylene means a straight chain, branched and/or cyclic hydrocarbon from 1 to
20 carbon atoms. Alkyl moieties having from 1 to 5 carbons are referred to as "lower alkyl" and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, and isobutyl.
Cycloalkyl or cycloalkylene represents a 3-14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic or one of the bicyclic rings is saturated or partially unsaturated and may optionally further comprise a -C(O)- ring member, and the other ring may be aromatic, saturated or partially unsaturated and may include one to three ring members selected from -C(=O), -N(R20)q-, -O- and S(O)r where R20 is H or Ci_6-alkyl, q is 0-1 and r is 0-2;
Aryl or arylene represents a 6-14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic or one of the bicyclic rings is aromatic and the other ring may be aromatic, saturated or partially unsaturated and may include one to three ring members selected from -C(O), -N(R19)q-, -O- and S(O)r where R19 is H or Ci_6-alkyl, q is 0-1 and r is 0-2;
Heteroaryl or heteroarylene represents a 5-14 membered monocyclic or bicyclic ring, wherein the monocyclic or one of the bicyclic rings is an aromatic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, and the other ring may be aromatic, saturated or partially unsaturated, and may include one to three ring members selected from -C(O), -N(R21)q-, -O- and S(O)r where R21 is H or Ci_6-alkyl, q is 0-1 and r is 0- 2; and
Heterocycloalkyl or heterocycloalkylene represents a 3-14 membered monocyclic or bicyclic ring, wherein the monocyclic or one of the bicyclic rings is a saturated or partially unsaturated group comprising one or two ring members selected from - N(R22)-, -O- and -S(O)1- and may optionally further comprise a -C(O)- ring member, and the other ring may be aromatic, saturated or partially unsaturated, and may include one to three ring members selected from -C(=O), -N(R23)q-, -O- and S(O)r where R22 or R23 is H or Ci_6-alkyl, q is 0-1 and r is 0-2.
2. The compound according to claim 1 where X represents -N (H)-.
3. The compound according to claim 1 or claim 2 where R1 represents phenyl substituted in the 2- and 4- positions.
4. The compound according to any one of claims 1-3, where R1 represents A- bromo-2-fluorophenyl, or 4-iodo-2-fluorophenyl.
5. The compound according to any of claims 1-4 where Y represents D, and D represents a group selected from -C(O)-,-CO2-, C(O)N(H)O-, -C(O)N(Ci-6. alkyl)O-, -C(O)N(H)- or -C(O)N(C i-e-alkyl)-.
6. The compound according to any one of claims 1-4, where R2 represents -COH-, -CO2H, -CO2Et, CON(H or CH3)OR7a, where R7a represents methyl, ethyl, cyclopropylmethyl, 2-ethenyloxyethyl, 2-hydroxyethyl, or 2,3- dihydroxypropyl, -CON(H or CH3)-R7b, where R7b represents H, methyl, ethyl, cyclopropylmethyl, 2-methoxy ethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetylaminomethyl, 2-dimethylaminoethyl, cyclopentyl or 2-thiazolyl, or R2 represents oxadiazolylamino.
7. The compound according to any of claims 1-4, or 6 where R2 represents C0NH0R7a where R7a represents cyclopropylmethyl, or 2-hydroxyethyl.
8. The compound according to any of claims 1-4 where -E- represents cycloalkyl, a 5-membered heteroarylene or 5-membered heterocycloalkylene which may be substituted or unsubstituted.
9. The compound according to any of claims 1-4 or 8, where E represents cyclopentyl, thiazole, or oxadiazole which may be substituted or unsubstituted.
10. The compound according to any one of claims 1-9, where R3 and R4 represent H.
11. The compound according to any one of claims 1-10, where R is H, methyl, ethyl, chloro, or fluoro.
12. The compound according to any of claims 1-8 where R5 is methyl.
13. The compound according to any one of claims 1-12, where Z is O.
14. The compound according to any one of claims 1-13, where m and n are both 1. or one of m and n is 1 and the other is 2.
15. A compound of formula Id:
Figure imgf000191_0001
and salts thereof, wherein:
Rd1 represents H, halogen, Ci_3-alkyl, or Ci_3-haloalkyl;
Rd2 represents H, cyano, or the group -Y-Rd5;
Rd3 and Rd4 independently represent hydroxyl, cyano, nitro, Ci-6.alkyl, C2-6-alkenyl, C2-β- alkynyl, Ci-6-alkoxy, C2-6-alkenyloxy, C2-6-alkynyloxy, halogen, Ci-6-alkylcarbonyl, carboxy, Ci-6_alkoxycarbonyl, amino, Ci-6-alkylamino, di-Ci-6-alkylamino, Ci-6-alkylaminocarbonyl, di- Ci-6-alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6-alkyl)amino, Cp6. alkylsulfonylamino, Ci-6-alkylsulfonyl(Ci-6-alkyl)amino, Ci-6-thioalkyl, Ci-6-alkylsulfmyl, Cp6. alkylsulfanyl, Ci-6.alkylsulfonyl, aminosulfonyl, Ci-6.alkylaminosulfonyl and di-Crβ- alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci-6_alkoxy, amino, Ci-6-alkylamino, di-Crβ- alkylamino or cyano; Y represents a group selected from -D-, -E-, -D-E-, or -E-D-;
D represents a group selected from -N(Rd8)-, -CO-,-CO2-, -SO-, -SO2-, CON(Rd j9y\)O-, - CON(Rd10)-, -N(Rd1 ^SO2-, -N(Rd12)So2NRd13-, -SO2N(Rd14)-, -N(Rd15)CO-, - N(Rd16)CON(Rd17)-, -N(Rd18)CO-, or -C(=NH)N(Rd19)-;
E represents a monocyclic arylene, heteroarylene, cycloalkylene or heterocycloalkylene, wherein said rings are optionally substituted by one or more groups independently selected from List 1 as defined herein;
Rd5 represents H, d-β-alkyl, C2-6_alkenyl C2-6_alkynyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein Rd5 when not H is optionally substituted by one to three groups independently selected from halogen, cyano, hydroxyl, Ci_6-alkoxy, C2-C6-alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci-βhaloalkyl, amino, Ci_6alkylamino, di-Ci_6alkylamino, Ci_6acylamino, Ci_6acylCi_6 alkylamino, monocyclic cycloalkyl or monocyclic heterocycloalkyl, where said rings may be optionally substituted by one or two groups independently selected from halogen, cyano, hydroxyl, Ci_6.alkoxy, C2-C6- alkenyloxy, C2-C6-alkynyloxy, Ci_6-thioalkyl, Ci_6-haloalkyl, amino, Ci_6-alkylamino, di- Ci_6-alkylamino, Ci_6-acylamino and C i_6-acylCi_6- alkylamino;
Rd6 and Rd7 independently represent hydroxyl, cyano, nitro, Ci-6.alkyl, C2-6.alkenyl, C2-6. alkynyl, d-6-alkoxy, C2-6_alkenyloxy, C2-6_alkynyloxy, halogen, Ci-6.alkylcarbonyl, carboxy, Ci-6_alkoxycarbonyl, amino, Ci-6.alkylamino, di-Ci-6.alkylamino, Ci-6-alkylaminocarbonyl, di- Ci-6-alkylaminocarbonyl, Ci-6-alkylcarbonylamino, Ci-6-alkylcarbonyl(Ci-6-alkyl)amino, Cp6. alkylsulfonylamino, Ci-6-alkylsulfonyl(Ci-6.alkyl)amino, Ci-6-thioalkyl, Ci-6.alkylsulfinyl, Cp6. alkylsulfanyl, Ci-6.alkylsulfonyl, aminosulfonyl, Ci-6.alkylaminosulfonyl and di-Ci-6- alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted by one or more halogen, hydroxyl, Ci-6.alkoxy, amino, Ci-6-alkylamino, di-Ci-6. alkylamino or cyano;
j and g independently represent O, 1, 2, or 3; Rd8, Rd9, Rd10, Rd11, Rd12, Rd13, Rd14, Rd15, Rd16, Rd17, Rd18, and Rd19 are independently H or Chalky;
Alkyl or alkylene means a straight chain, branched and/or cyclic hydrocarbon from 1 to 20 carbon atoms. Alkyl moieties having from 1 to 5 carbons are referred to as "lower alkyl" and examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, and isobutyl.
Cycloalkyl or cycloalkylene represents a 3-14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic or one of the bicyclic rings is saturated or partially unsaturated and may optionally further comprise a -C(O)- ring member, and the other ring may be aromatic, saturated or partially unsaturated and may include one to three ring members selected from -C(=O), -N(R20)q-, -O- and S(O)r where R20 is H or d-6-alkyl, q is 0-1 and r is 0-2;
Aryl or arylene represents a 6-14 membered monocyclic or bicyclic carbocyclic ring, wherein the monocyclic or one of the bicyclic rings is aromatic and the other ring may be aromatic, saturated or partially unsaturated and may include one to three ring members selected from -C(O), -N(R19)q-, -O- and S(O)r where R19 is H or Ci_6-alkyl, q is 0-1 and r is 0-2;
Heteroaryl or heteroarylene represents a 5-14 membered monocyclic or bicyclic ring, wherein the monocyclic or one of the bicyclic rings is an aromatic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, and the other ring may be aromatic, saturated or partially unsaturated, and may include one to three ring members selected from -C(O), -N(R21)q-, -O- and S(O)r where R21 is H or Ci_6-alkyl, q is 0-1 and r is 0- 2; and
Heterocycloalkyl or heterocycloalkylene represents a 3-14 membered monocyclic or bicyclic ring, wherein the monocyclic or one of the bicyclic rings is a saturated or partially unsaturated group comprising one or two ring members selected from - N(R22)-, -O- and -S(O)1- and may optionally further comprise a -C(O)- ring member, and the other ring may be aromatic, saturated or partially unsaturated, and may include one to three ring members selected from -C(=O), -N(R23)q-, -O- and S(O)r where R22 or R23 is H or Ci_6-alkyl, q is 0-1 and r is 0-2.
16. The compound according to any one of claims 1-15 for use in therapy.
17. A method of treating a disease, disorder or syndrome associated with MEK inhibition, said method comprising administering a compound according to any one of claims 1-15 or its prodrug or pharmaceutical composition comprising the compound of formula 1 or its prodrug and pharmaceutically acceptable excipients to a subject in need thereof.
18. The method of treating as claimed in claim 17, wherein the disease, disorder or syndrome is hyperproliferative in a subject, wherein subject is an animal including humans, selected from a group comprising cancer and inflammation.
19. The compound of formula I, method of treating disease, disorder or syndrome associated with MEK inhibition substantially as herein described along with examples.
20. A pharmaceutical composition comprising a compound of formula I according to any of claims 1-15 and a pharmaceutically acceptable carrier or excipient.
21. A pharmaceutical composition comprising a compound of formula I according to any of claims 1-15 in combination with a second active agent, and a pharmaceutically acceptable carrier or excipient.
22. A compound selected from
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l, 2, 3, 5-tetrahydro-indolizine-8- carboxylic acid ethyl ester;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ; 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropyl-methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid dimethyl amide;
7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8- carboxylic acid methoxyl amide;
7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8- carboxylic acid amide;
7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8- carboxylic acid ethoxy amide;
7-(4-bromo 2-fluoro-phenylamino) -5-oxo-l,2,3,5-tetrahydro indolizine 8- carboxylic acid (2-hydroxy ethyl) amide;
7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine 8- carboxylic acid methyl amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid methoxy-ethyl-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carbaldehyde
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid cyclopropyl methoxy-amide;
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-
8-carboxylic acid amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropyl methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropyl methoxy-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2 -vinyl oxy-ethoxy)-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethoxy-amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid ethyl ester;
2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid;
2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid-cyclopropyl-methoxyamide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid-(2-vinyloxy-ethoxy)-amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid methoxy amide;
2-(4-bromo-2-fluoro-phenylamino)-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-l- carboxylic acid ethoxy amide;
7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetyrahydro- indolizine-8-carboxylic acid (2-hydroxyethoxy)amide; 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (3-hydroxy-propyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-methoxy-ethyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-acetylamino-ethyl)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-dimethylamino-ethyl)-amide; 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopentylamide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethylamide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (3-methoxy-propyl)-amide; 7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethyl ester;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid methoxy-amide;
7-(2-Fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid ethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid (2,3-dihydroxy-propoxy)-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-chloro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2,3-dihydroxy-propoxy)-amide; 6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid cyclopropylmethoxy-amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid methoxy- amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid ethoxy-amide;
6-Chloro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid (2,3-dihydroxy-propoxy)-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid thiazol-2-ylamide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (3-hydroxy-propyl)-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid dimethylamide;
7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-methoxy-ethyl)-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-acetylamino-ethyl)-amide; 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (pyridin-2-ylmethyl)-amide; 6-Fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid;
6-Fluoro-7-(2-fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy-amide; 6-Fluoro-7-(2-fluoro-4-methylsulfanyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy- amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-[5-(2-hydroxy-ethylamino)-
[l,3,4]oxadiazol-2-yl]-2,3-dihydro-lH-indolizin-5-one;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid methoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide;
7-(4-Bromo-2-methyl-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid;
7-(4-Bromo-2-methyl-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy- amide;
7-(4-Bromo-2-methyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid;
7-(4-Bromo-2-methyl-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide;
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-8-(3-hydroxy-3-piperidin-2-yl- azetidine-l-carbonyl)-2,3-dihydro-lH-indolizin-5-one hydrochloride;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(3-hydroxy-3-piperidin-2-yl- azetidine- 1 -carbonyl)-2,3-dihydro- lH-indolizin-5-one;
6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-8-(3-hydroxy-3-piperidin-2-yl- azetidine- 1 -carbonyl)-2,3-dihydro- lH-indolizin-5-one;
Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo- l,2,3,5-tetrahydro-indolizin-8-yl]-amide;
N-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizin-8-yl]-N,N-dimethyl-amino-sulfonamide;
2,3-Dihydroxy-propane-amino-sulfonicacid-[7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; l-[7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro- indolizin-8-ylsulfamoyl]-pyrrolidine-2-carboxylic acid; 2-Hydroxymethyl-pyrrolidine-l -sulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-but-3-enyl)-2,3- dihy dro - 1 H-indo lizin-5 -one ;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(l-hydroxy-allyl)-2,3-dihydro-
1 H-indo lizin-5 -one;
7-(4-Bromo-2-fluoro-phenylamino)-8-(2,3-dihydroxy-propionyl)-6-fluoro-2,3- dihy dro - 1 H-indo lizin-5 -one ;
7-(4-Bromo-2-fluoro-phenylamino)-6-fluoro-8-(2-hydroxy-acetyl)-2,3-dihydro-
1 H-indo lizin-5 -one;
7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester;
7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid;
7-(2-Fluoro-4-trifluoromethyl-phenylamino)-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy- amide;
7-(2-Fluoro-4-methoxy-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carboxylic acid cyclopropylmethoxy-amide;
7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine-8- carbaldehyde oxime;
7-(4-Bromo-2-fluoro-phenylamino)-8-(3-hydroxy-3-pyridin-2-yl-azetidine-l- carbonyl)-2,3-dihydro-lH-indolizin-5-one;
7-(4-Bromo-2-fluoro-phenylamino)-8-(3-hydroxy-azetidine-l-carbonyl)-2,3- dihy dro - 1 H-indo lizin-5 -one ;
3-(4-Bromo-2-fluoro-phenyl)- 1 -methanesulfonyl- 1 ,6,7,8-tetrahydro-3H- 1 ,3,5a- triaza-as-indacene-2,5-dione;
Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5- tetrahydro -indo lizin- 8 -y 1] -amide ;
N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8- yl]-4-fluoro-benzenesulfonamide;
[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]- carbamic acid tert-butyl ester; Cyclohexanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5- tetrahydro -indo lizin- 8 -y 1] -amide ;
N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8- yl]-4-trifluoromethyl-benzenesulfonamide;
N-[7-(4-Bromo-2-fluoro-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8- yl]-N,N-dimethylaminosulfonamide;
5-(4-Bromo-2-fluoro-phenylamino)-2,2-dimethyl-7-oxo-3a,7,8,8a-tetrahydro- 1 ,3-dioxa-7a-aza-cyclopenta[a]indene-4-carboxylic acid; 7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester;
7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclopropylmethoxy- amide; 7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide; 7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclobutylmethoxy-amide; 7-(4-Bromo-2-fluoro-phenylamino)-l,2-dihydroxy-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid (3-hydroxy-2-methyl-propoxy)-amide; 1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [6-fluoro-7-(2-fluoro-4- iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; 1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; 1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(4-bromo-2-fluoro- phenylamino)-6-fluoro-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; 6-Fluoro-7-(2-fluoro-4-iodo-phenylamino)-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid (2,3-dihydroxy-propoxy)-amide; 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l, 2, 3, 5-tetrahydro- indolizine-8-carboxylic acid cyclopropyl methoxy amide; 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l , 2,3, 5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide; 7-(2-Fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid cyclobutylmethoxy-amide; 1 -(2,3-Dihydroxy-propyl)-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo- phenylamino)-6-methyl-5-oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide; and Cyclopropanesulfonic acid [7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5- oxo-l,2,3,5-tetrahydro-indolizin-8-yl]-amide, or pharmaceutically acceptable salts thereof.
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WO2011054828A1 (en) * 2009-11-04 2011-05-12 Novartis Ag Heterocyclic sulfonamide derivatives useful as mek inhibitors
AU2010317167B2 (en) * 2009-11-04 2012-11-29 Novartis Ag Heterocyclic sulfonamide derivatives useful as MEK inhibitors
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US9718879B2 (en) 2012-01-26 2017-08-01 Imperial Innovations Ltd. Methods of treating pain by inhibition of VGF activity
US9555035B2 (en) 2012-03-14 2017-01-31 Lupin Limited Heterocyclyl compounds as MEK inhibitors
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WO2016009306A1 (en) 2014-07-15 2016-01-21 Lupin Limited Heterocyclyl compounds as mek inhibitors
WO2016035008A1 (en) 2014-09-04 2016-03-10 Lupin Limited Pyridopyrimidine derivatives as mek inhibitors
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WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use

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